The Breast Cancer Research Foundation recently announced that Dr. Richard Pestell and Dr. Andrew Quong received unanimous approval for studies in breast cancer, the second most prevalent cancer-related cause of death in women in the United States.
Beginning October 1, 2013, Dr. Pestell will receive $240,000 to continue the “Molecular Genetic determinants of Breast Cancer Stem Cells” study and Dr. Quong will receive $240,000 to continue the “Clinical Proteomics for Breast Cancer Diagnostics” study.
Dr. Pestell’s study will focus on basal breast cancer including triple negative breast cancer, defined by the absence of three receptors (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2]). Triple negative breast cancer is prominent among African-American women, and currently no targeted therapies for this type of breast cancer exist. Within human breast cancer a subset of cells have characteristics of stem cells (BTIC), which may contribute to recurrence and therapeutic resistance. The mechanism by which the gene DACH1 inhibits BTIC is being determined as a new approach to enhance therapeutic responsiveness. Dr. Pestell’s findings over the last year that DACH1 binds to and enhances function of the p53 tumor suppressor, but fails to bind mutations of p53 identified in human breast cancer, adds further weight to the original hypothesis that DACH1 is a breast tumor suppressor. Dr. Pestell’s studies in 2012-2013 will continue to define the role of endogenous DACH1 as a breast cancer suppressor.
Support from BCRF has also allowed Dr. Quong to complete his studies examining changes in protein levels in breast tumors. From these observed changes, Dr. Quong’s team found changes in the metabolism of tumor cells that are related to the local microenvironment of the tumor. These changes in metabolism can potentially be exploited for both imaging and drug development. In addition, Dr. Quong has continued his work identifying markers that are indicators of toxicity and response to therapy.
In 2012-2013, the goal of Dr. Quong’s research is to determine new strategies for patient treatment that include radiation therapy. By measuring the protein and gene expression in tumors, his will use this information for choosing treatment and also monitoring the patients’ response to treatment both for effectiveness and adverse side effects.
A study led by investigators from Thomas Jefferson University’s Kimmel Cancer Center has discovered molecular clues that may help physicians therapeutically target inflammatory breast cancer (IBC), a highly aggressive form of breast cancer.
Their study, reported in the June 21 online issue of Breast Cancer Research and Treatment, identified two molecules (ALK and FAK1) involved in the IBC cancer pathway. Drugs already exist that inhibit both of these two cancer-promoting proteins at the same time, which the researchers are now testing in animal preclinical studies.
“Women diagnosed with inflammatory breast cancer are in great need of therapies that are tailored to this aggressive form of breast cancer. Survival rates are much lower than for other forms of breast cancer,” says the study’s lead author Sandra V. Fernandez, Ph.D., Assistant Professor in the Medical Oncology department at Jefferson.
IBC is a particularly aggressive and highly metastatic form of breast cancer characterized by very rapid onset of progression— weeks to a few months — and metastasis that spreads quickly to the brain, bones, and soft tissues. The three-year survival rate is 40 percent for IBC patients compared with 85 percent in other forms of breast cancer. Additionally, IBC patients are younger when diagnosed.
The disease is also difficult to diagnose because it appears as redness and swelling of the breast. There are no classic tumor masses.
“Because of how this cancer looks, physicians often think it is dermatitis, or inflammation, or an infection, such as mastitis. I know of many patients who were misdiagnosed from the start, and by the time they were referred to an oncologist, their cancer had progressed,” says the study’s senior investigator, Massimo Cristofanilli, MD, FACP, Professor of Medical Oncology and Director of the Jefferson Breast Care Center.
“We need to improve both diagnosis and treatment of this cancer, which is on the rise for reasons that are not understood,” he says.
The advances reported in the study were possible because the research team developed a new animal model of IBC, derived from tumor cells from a patient with metastatic triple negative (estrogen receptor-negative, progesterone receptor-negative, Her2-negative) inflammatory breast cancer under an IRB-approved study. At the present, there are few animal models to study this particular disease.
In addition to identifying some of the pathways involved in IBC, the researchers were able to characterize the pattern of spread of the disease, which moved quickly to organs and the brain. They found that clumps of the cancer — not tumor masses — obstruct lymphatic channels in the breast, causing the swelling of breast tissues.
“This animal model is a really important tool to use to study IBC progression and metastasis, and to test potentially beneficial drugs,” says Dr. Fernandez.
Researchers from the University of Texas M D Anderson Cancer Center and Fox Chase Cancer Center contributed to the research.
The study was supported by the American Airlines-Komen for the Cure Foundation Promise Grant KGO81287, NIH NCI 1R01 CA 138239, and the Inﬂammatory Breast Cancer Foundation.
The authors declare that they have no conflicts of interest.
For more information, contact Jackie Kozloski, 215-955-5296, firstname.lastname@example.org.
Recent studies by researchers at Thomas Jefferson University’s Kimmel Cancer Center have shown a gene known to coordinate initial development of the eye (EYA1) is a powerful breast tumor promoter in mice. The gene EYA1 was also shown to be overexpressed in a genetic breast cancer subtype called luminal B.
The scientists found that excess activity of this gene —EYA1 — also enhances development of breast cancer stem cells that promote resistance to cancer therapy, recurrence, and poor survival.
Because EYA1 is an enzyme, the scientists are now working to identify a natural compound that could shut down EYA1 activity, says Richard Pestell, M.D., Ph.D., Director of Kimmel Cancer Center.
“It was known that EYA1 is over-expressed in some breast cancers, but no one knew what that meant,” he says. “Our studies have shown the enzyme drives luminal B breast tumor growth in animals and the enzyme activity is required for tumor growth.”
In a mouse model of aggressive breast cancer, the research team targeted a single amino acid on the EYA1 phosphatase activity. They found that inactivating the phosphatase activity of EYA1 stopped aggressive human tumors from growing.
“We are excited about the potential of drug treatment, because it is much easier to develop a drug that targets a phosphatase enzyme like EYA1, than it is to target a gene directly,” he says.
Tracing how EYA1 leads to poor outcomes
The study, which was published in the May 1 issue of Cancer Research, examined 2,154 breast cancer samples for the presence of EYA1. The researchers then linked those findings to patient outcomes. They found a direct relationship between increased level of EYA1 and cyclin D1 to poor survival.
They then chose one form of breast cancer —luminal B — and traced the bimolecular pathway of how EYA1 with cyclin D1 increases cancer aggressiveness. Luminal B breast cancer, one of five different breast cancer subtypes, is a hormone receptor-positive form that accounts for about 20 percent of human breast cancer. It is more aggressive than luminal A tumors, a hormone receptor-positive cancer that is the most common form of breast cancer.
Their work delineated a string of genes and proteins that are affected by EYA1, and they also discovered that EYA1 pushes an increase in formation of mammospheres, which are a measure of breast cancer stem cells.
“Within every breast cancer are breast cancer stem cells, which give rise to anti-cancer therapy resistance, recurrence and metastases,” Dr. Pestell says. “We demonstrated in laboratory experiments that EYA1 expression increase the number of mammospheres and other markers of breast cancer stem cells.”
“As the EYA1 phosphatase activity drove breast cancer stem cell expansion, this activity may contribute to worse survival,” he says.
This study was supported in part by the NIH grants RO1CA132115, R01CA70896, R01CA75503, R01CA86072 and P30CA56036 (RGP), a grant from the Breast Cancer Research Foundation (RGP), a grant for Dr. Ralph and Marian C. Falk Medical Research Trust (RGP), Margaret Q. Landenberger Research Foundation, the Department of Defense Concept Award W81XWH-11-1-0303.
Study co-authors are, from Kimmel Cancer Center: first author Kongming Wu, Zhaoming Li, Shaoxin Cai, Lifeng Tian, Ke Chen, Jing Wang and Adam Ertel; Junbo Hu, from Huazhong University of Science and Technology, China; and Ye Sun, and Xue Li from Boston Children’s Hospital.
For more information: Jackie Kozloski, 215-955-5296, email@example.com.
Mary Louise Leuters is a two-time breast cancer survivor and president of the Ladies of Port Richmond, a local group of breast cancer survivors who have raised over $400,000 for breast cancer research in the last nine years.Nearly 300,000 American women will be diagnosed with breast cancer this year, and 40,000 will die from it, according to the American Cancer Society. There are nearly three million survivors.The Ladies of Port Richmond host a local walk each year along with many fundraising events including bake sales and church breakfasts.In an interview with the Philadelphia Inquirer, Richard Pestell, MD, director of the Kimmel Cancer Center at Jefferson, explains that the money is especially valuable because it comes with no strings attached. Jefferson researchers have used it as seed money – almost impossible to find otherwise – to do preliminary research that has helped win National Cancer Institute grants worth millions. He adds, ”There’s been a tremendous return on their efforts.”
Read the full “The fighting ladies of Port Richmond” story.
Massimo Cristofanilli, M.D., FACP, an internationally renowned breast cancer researcher and clinician, has been appointed Director of the Jefferson Breast Care Center at the Kimmel Cancer Center (KCC) and Thomas Jefferson University and Hospitals.
With more than 25 years of clinical, basic science and educational experience, Dr. Cristofanilli will also serve as Deputy Director of Translational Research at the KCC.
Prior to joining Jefferson, Dr. Cristofanilli served as chairman of the department of medical oncology at Fox Chase Cancer Center and head of the center’s Inflammatory Breast Cancer Clinic. Before that, he founded and served as Executive Director of the Morgan Welch Inflammatory Breast Cancer Program and Clinic at The University of Texas M.D. Anderson Cancer Center in Houston.
Dr. Cristofanilli is a widely-recognized leader in the translational research and treatment of inflammatory breast cancer (IBC), the rare and aggressive form of breast cancer in which cancer cells block lymph vessels in the skin of the breast. Moreover, he has recognized expertise in the development of novel diagnostic and prognostic markers in primary and metastatic breast cancer (MBC).
“Dr. Cristofanilli is a proven leader whose translational research expertise will fit in perfectly with the overall mission of the KCC to link our already excellent basic science in breast cancer with more patient-directed therapies in a time-efficient manner,” said Richard G. Pestell, M.D., Ph.D., Director of the KCC and Chair of the Department of Cancer Biology and Vice President for Oncology Services at Jefferson. “We look forward to tackling some of the most innovative questions in breast cancer precision oncomedicine with cutting edge research and the latest clinical trials.”
Dr. Cristofanilli’s research aims to improve personalized medicine for breast cancer patients, focusing on molecular targeted agents, biomarkers and gene therapies, and bridging the gap between the bench and bedside in a more practical and smarter way. A forte of Dr. Cristofanilli is his team-based and multidisciplinary approach to medicine.
His 2004 study published in The New England Journal of Medicine on circulating tumor cells (CTCs)—found to be a predictor of progression-free survival and overall survival in MBC patients—sparked a slew of subsequent preclinical and clinical investigations that continue to further our knowledge and molecular understanding of the metastatic process with the potential to impact the treatment and improve the prognosis of these patients affected by recurrent disease.
Recently, he presented a study at the 2012 San Antonio Breast Cancer Symposium on commercially-available genomic tests and their ability to better classify tumor subtypes in breast cancer to help guide treatment plans.
“We’re proud that Jefferson is the new home for Dr. Cristofanilli, whose work in cancer research and in the clinic goes unmatched and whose passion to initiate and grow programs speaks for itself, particularly for aggressive forms of breast cancer,” said Neal Flomenberg, M.D., Chair of the Department of Medical Oncology at Jefferson. “We’re looking forward to this new chapter at the Jefferson Breast Care Center and the KCC, where his experience in compassionate clinical care and cutting edge research will better serve the institution and ultimately the patients in the region and beyond.”
Dr. Cristofanilli received his medical degree from the University of La Sapienza in Rome, Italy, where he also completed a fellowship in medical oncology. He completed an internship at the Cabrini Medical Center in New York, as well as his residency in internal medicine. That was followed by a fellowship in medical oncology at The University of Texas M.D. Anderson Cancer Center.
Dr. Cristofanilli is Board Certified by the American Board of Medical Oncology and the European Society for Medical Oncology.
“Jefferson, as an institution, has a tradition, but at the same time is always projecting towards the future, forever expanding upon research and clinical programs, bringing innovative technologies into the lab and clinic, and attracting new physicians and patients,” said Dr. Cristofanilli. “I want to bring my vision to Jefferson and look forward to us to being able to grow together.”
The Jefferson Breast Care Center was founded in 2006 and is one of 466 centers in the nation accredited by the National Accreditation Program for Breast Centers. The Center gives the patient a comprehensive experience where surgery, medical oncology, radiation oncology, radiology, pathology risk assessment / genetics, social work and a breast care navigator are all working together with the patient at the center of care.
Jefferson Opens Calorie Restriction Trial for Early Stage Breast Cancer Patients on Radiation Therapy
Jefferson’s Kimmel Cancer Center will begin a first-of-its-kind clinical trial that uses calorie restriction to help treat early stage breast cancer patients undergoing radiation therapy.
Evidence suggests that reducing patients’ calorie intake could help shrink tumors and improve survival because it enhances the effectiveness of radiation therapy, the team explains in a recent review published in the Oncologist.
“In our research, we’ve seen a 30 percent reduction in tumor size in mice, and they live much longer than mice not on a diet,” said Nicole Simone, M.D., Principal Investigator and Assistant Professor of Radiation Oncology at Thomas Jefferson University and Hospitals. “The next step is to investigate if early stage breast cancer patients are able to adhere to caloric restriction while on radiation. This will then allow us to determine others benefits and factors, such as toxicity, recurrence, and survival.”
Until now, the use of calorie restriction to treat cancer or augment standard cancer treatment, such as radiation therapy, has received little attention, with few trials underway in the U.S. Jefferson’s trial, however, is the first in breast cancer patients.
The study is being partly funded by a donation from the Ladies of Port Richmond, a local breast cancer group that raises awareness and funds for research.
Caloric restriction has been shown to alter molecular pathways that make cancer cells more susceptible to radiation, enhancing its effectiveness and thus shrinking tumors and improving survival in mice. What’s more, clinical evidence over the last several decades has shown a link between cancer incidence and calorie restriction.
Beginning in February, Jefferson will begin enrolling 40 women on a calorie reduction diet (a 25 percent reduction of the patients typical total intake) while undergoing treatment. Stage 0 and I breast cancer patients who are not diabetic but who are candidates for breast conserving therapy will be given dietary counseling and guidance to carry out a liquid diet 36 hours prior to lumpectomy and then a calorie reduction of 25 percent will be done during radiation therapy.
Calorie restriction will start the week of radiation planning and continue for the six weeks of radiation, for a total of 10 weeks. Patients will keep a nutritional journal, have counseling in Jefferson’s own Myrna Brind Center of Integrative Medicine to tailor the diet reduction for each individual patient and also meet with counselors during weekly visits.
For the trial, the feasibility of treating breast cancer patients with a calorie-restriction diet modification in conjunction with standard radiation will be assessed. Acute toxicity as per National Cancer Institute Common Toxicity Criteria, quality of life, local recurrence, progression-free survival, distant metastases and overall survival will be also assessed.
In the lab, calorie restriction has been used prior to implantation of tumor cells in mouse breast cancer models and has been shown to slow or even prevent tumor growth.
Dr. Simone’s laboratory has investigated calorie restriction as a treatment modality, implanting tumors in mice prior to initiation of the diet to mimic the use of a diet in a newly diagnosed patient. For the second approach, calorie restriction was administered with cytotoxic therapy to determine the value of calorie restriction as part of a combination therapy.
Preliminary data demonstrated that calorie restriction repressed tumor growth when administered concurrently with radiation in two types of breast cancer: triple negative breast cancer, which has a propensity for metastases and locally aggressive breast cancer.
Calorie restriction alters molecular pathways, including the insulin and AMP-kinase pathway, the researchers posit, leaving cancer cells more sensitive to radiation therapy. Both pathways have been shown to play a role in breast cancer cell proliferation and progression of disease.
Dr. Simone presented the work at the 2012 American Society for Radiation Oncology, and has published several studies on the topic in Cell Cycle and International Journal of Breast Cancer
“Dieting is likely an effective method to enhance the cytotoxicity of radiation therapy because of the overlapping induction of molecular profiles, and it may also provide a beneficial means of improving the overall health and metabolic profiles of patients,” said Dr. Simone. “This trial could provide evidence to implement calorie restriction into the care of cancer patients in treatment. What’s more, it may provide a cost-effective addition to current treatment modalities that enhances cancer therapy while minimizing side effects.”
A natural substance found in the surrounding tissue of a tumor may be a promising weapon to stop triple negative breast cancer from metastasizing.
A preclinical study published in PLOS ONE September 19 by Thomas Jefferson University researchers found that decorin, a well-studied protein known to help halt tumor growth, induces a series of tumor suppressor genes in the surrounding tissue of triple negative breast cancer tumors that help stop metastasis.
“These findings provide a new paradigm for decorin, with great implications for curbing tumor growth by inducing new tumor suppressor genes within the tumor microenvironment, and for the discovery of novel gene signatures that could eventually help clinical assessment and prognosis,” said senior author Renato V. Iozzo, M.D., Professor of Pathology, Anatomy and Cell Biology, at Thomas Jefferson University.
Triple negative breast cancer is the most deadly of breast cancers, with fast-growing tumors, that disproportionately affect younger and African-American women. Today, no such marker is applied in care of triple negative breast cancer, and as a result, patients are all treated the same.
“Originally, we thought that decorin was affecting the tumor, but, surprisingly, decorin affects the so-called tumor microenvironment, where malignant cells grow and invade, igniting genes to stop such growth,” said Dr. Iozzo, who is also a member of Jefferson’s Kimmel Cancer Center. “Absence of decorin in the microenvironment could explain metastasis in some patients, where higher levels of the protein may keep cancer from spreading.”
In the study, 357 genes were found to be induced by the increased presence of decorin, but more interestingly, the researchers discovered that three of these genes, which were previously unlinked to triple negative breast cancer, were tumor suppressor genes affecting the tumor microenvironment, including Bmp2K, Zc3hav1, and PEG3.
Decorin is a naturally occurring substance in the connective tissue where, among other roles, it helps regulate cell growth by interacting with growth factors and collagen. A decade ago, Dr. Iozzo and his team discovered that decorin, a cell protein, and specifically, a proteoglycan, is increased in the matrix surrounding tumor cells. They also discovered that decorin causes production of a protein, p21, which also can arrest cell growth. However, decorin’s role in breast cancer and the mechanism behind its anti-tumor properties remained elusive.
For this study, researchers aimed to investigate the impact of decorin in triple negative breast cancer tumors using human cell lines in mice, as well analyze gene expression activity in the tumor microenvironment.
Tumors treated with decorin were found to have a decreased volume of up to 50 percent after 23 days. Using a sophisticated microarray technique, the researchers then analyzed the mouse tumor microenvironment, finding increased expression of 357 genes, three of which are the tumor suppressor genes of interest.
These results demonstrate a novel role for decorin in reduction or prevention of tumor metastases that could eventually lead to improved therapeutics for metastatic breast cancer.
“Here, we have a molecule that can turn a tumor microenvironment from a bad neighborhood to a clean neighborhood by inducing genes in that neighborhood to stop growth and prevent the tumor from metastasizing,” said Dr. Iozzo.
Breast cancer patients whose tumors lacked the retinoblastoma tumor suppressor gene (RB) had an improved pathological response to neoadjuvant chemotherapy, researchers at Thomas Jefferson University Hospital and the Kimmel Cancer Center at Jefferson report in a retrospective study published in a recent online issue of Clinical Cancer Research.
Many breast cancer patients undergo neoadjuvant therapy to reduce the size or extent of the cancer before surgical intervention. Complete response of the tumor to such treatment signifies an improved overall prognosis. Today, no marker is applied to identify tumors which will respond to such treatment, and as a result, only a subset of patients exhibit benefit from it.
“We found that loss of RB was associated with better pathological response rates in breast cancer patients—at various stages and representing multiple molecular subtypes—who were administered neoadjuvant chemotherapy,” said Agnieszka Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University.
Erik Knudsen, Ph.D, Professor of Cancer Biology and the Hilary Koprowski Chair in Cancer Biology, was excited that discoveries from his life-long research on the RB-pathway were making their way into the clinic. “This represents a potential new biomarker that could be used to tailor treatment plans for women considering neoadjuvant therapy and is a testament to the importance of cancer research,” he said.
For the study, researchers, including Gordon Schwartz, M.D., Director of the Jefferson Breast Care Center and Adam Ertel, Ph.D., Bioinformatics Specialist, Department of Cancer Biology, performed a combination of gene expression profiling to identify those with RB loss and direct histological analysis in over 1,000 breast cancer patients who had undergone neoadjuvant therapy. These patients represented distinct subtypes of breast cancer and were treated with multiple different therapeutic regimens.
RB loss was associated, the team found, with an improved response to all the neoadjuvant regimens investigated in the major subtypes of breast cancer.
“Together, these data indicate that the loss of RB, which occurs relatively frequently in locally advanced disease, could be a useful tool for defining patients who experience an improved response to neoadjuvant chemotherapy,” said Dr. Witkiewicz. “Based on these findings, we have initiated a prospective clinical trial at Jefferson, evaluating the association of RB and another marker, PTEN, with the response to neoadjuvant chemotherapy.”
The clinical trial is open to patients who have a diagnosis of triple negative breast cancer and are eligible for neoadjuvant chemotherapy. (clinicaltrials.gov/ct2/show/NCT01514565).
It has long been known that cancer is a disease of aging, but a molecular link between the two has remained elusive.
Now, researchers at the Kimmel Cancer Center at Jefferson (KCC) have shown that senescence (aging cells which lose their ability to divide) and autophagy (self-eating or self-cannibalism) in the surrounding normal cells of a tumor are essentially two sides of the same coin, acting as “food” to fuel cancer cell growth and metastasis.
Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the KCC, and his team previously discovered that cancer cells induce an oxidative stress response (autophagy) in nearby cells of the tumor microenvironment to feed themselves and grow.
In this study, senescent cells appear to have many of the characteristics of these autophagic cancer-associated fibroblasts and to be part of the same physiological process. In other words, normal neighboring cells that are becoming senescent or “old” are directly making food to “feed” the cancer. Aging literally fuels cancer cell growth.
Since senescence is thought to reflect biological aging, this research on autophagy-induced senescence may explain why cancer incidence dramatically increases exponentially with advanced age, by providing a “fertile soil” to support the anabolic growth of “needy” cancer cells.
The findings were reported in the June 15 issue of Cell Cycle.
“This research merges the two paradigms of aging and cancer, and it also brings in cell metabolism,” said Dr. Lisanti. “We provide genetic support for the importance of ‘two-compartment tumor metabolism’ in driving tumor growth and metastasis via a very simple energy transfer mechanism. Senescence and autophagy metabolically support tumor growth and metastasis.”
Simply put, aging is the metabolic engine that drives cancer growth.
To test this link, the researchers developed a genetically tractable model system to directly study the compartment-specific role of autophagy in tumor growth and metastasis. First, they took human fibroblasts immortalized with telomerase and transfected them with autophagy genes.
Next, they validated that these fibroblasts show features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, with increases in lactate and ketone production, mimicking the behavior of cancer-associated fibroblasts. They observed that autophagic-senescent fibroblasts promoted metastasis, when co-injected with human breast cancer cells, by more than 10-fold.
Thus, metastasis may be ultimately determined by aging or senescent cells in the tumor microenvironment, rather than by the cancer cells themselves. This finding completely changes how we view cancer as a disease.
This observation directly calls into question the longstanding notion that cancer is a cell-autonomous genetic disease. Rather, it appears that cancer is really a disease of host aging, which fuels tumor growth and metastasis, thus, determining clinical outcome. Normal aging host cells are actually the key to unlocking effective anti-cancer therapy.
In the study, the autophagic fibroblasts also showed features of senescence. What’s more, the senescent cells shifted toward aerobic glycolysis, and were primarily confined to the tumor stromal compartment.
Autophagy action is also clearly compartment specific, since the researchers showed that autophagy induction in human breast cancer cells resulted in diminished tumor growth. Therefore, selective induction of self-cannibalism in cancer cells is a new therapeutic target for the prevention of tumor growth and metastasis. In this strategy, cancer cells actually eat themselves, reversing tumor growth and metastasis.
To stop tumor growth and metastasis, researchers will need to “cut off the fuel supply” which is provided by aging senescent cells, before it gets to cancer cells by targeting autophagy and senescence in the tumor microenvironment.
These findings are paradigm shifting and will usher in a completely new era for anti-cancer drug development, according to the researchers. Such approaches for targeting the “autophagy-senescence transition” could have important implications for preventing tumor growth and metastasis, and effectively overcoming drug resistance in cancer cells.
“Rapidly proliferating cancer cells are energetically dependent on the aging host tumor stroma,” Dr. Lisanti said. “As such, removing or targeting the aging tumor stroma would then stop tumor growth and metastasis. Thus, the aging stroma is a new attractive metabolic or therapeutic target for cancer prevention.”
A clear byproduct of this research would also be the development new anti-aging drugs to effectively combat, stop or reverse aging, thereby preventing a host of human diseases, particularly cancer.
This work was supported by grants from the Breast Cancer Alliance the American Cancer Society, Young Investigator Award from the Margaret Q. Landenberger Research Foundation, grants from the NIH/NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660), and the Susan G. Komen Breast Cancer Foundation. Other grants include NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was supported by the NIH/ NCI Cancer Center Core grant P30-CA-56036 (to R.G.P.). This project is funded, in part, under a grant with the Pennsylvania Department of Health. This work was also supported, in part, by a Centre grant in Manchester from Breakthrough Breast Cancer in the UK and an Advanced ERC Grant from the European Research Council.
Thomas Jefferson University (TJU), the largest freestanding academic medical center in Philadelphia, is nationally renowned for medical and health sciences education and innovative research. Founded in 1824, TJU includes Jefferson Medical College (JMC), one of the largest private medical schools in the country and ranked among the nation’s best medical schools by U.S. News & World Report, and the Jefferson Schools of Nursing, Pharmacy, Health Professions, Population Health and the College of Graduate Studies. Jefferson University Physicians is TJU’s multi-specialty physician practice consisting of the full-time faculty of JMC. Thomas Jefferson University partners with its clinical affiliate, Thomas Jefferson University Hospitals.
Key References: Capparelli et al.
Researchers at the Kimmel Cancer Center, led by Dr. Richard G. Pestell have discovered that FDA-approved HIV drugs may stop triple-negative breast cancer from spreading to other organs in pre-clinical models.
These results were originally reported in Cancer Research.
The HIV drugs known as CCR5 antagonists may also help prevent aggressive breast cancers from metastasizing, researchers from the Kimmel Cancer Center at Jefferson suggest in a preclinical study published in a recent issue of Cancer Research.
Such drugs target the HIV receptor CCR5, which the virus uses to enter and infect host cells, and has historically only been associated with expression in inflammatory cells in the immune system. Researchers have now shown, however, that CCR5 is also expressed in breast cancer cells, and regulates the spread to other tissue.
What’s more, blocking the receptor with the CCR5 antagonists Maraviroc and Vicriviroc, two drugs that slow down the spread of the HIV virus by targeting the CCR5 co-receptor of the chemokine CCL5, also prevents migration and spread of breast cancer cells, the researchers found.
“These results are dramatic,” said Richard Pestell, M.D., Ph.D., FACP, Director of Jefferson’s Kimmel Cancer Center and Chair of the Department of Cancer Biology at Thomas Jefferson University, and study senior author. “Our team showed that the CCR5/CCL5 axis plays a key role in invasiveness, and that a CCR5 antagonist can slow down the invasion of basal breast cancer cells.”
“This suggests it may prove to be a viable adjuvant therapy to reduce the risk of metastasis in the basal breast cancer subtype,” he added.
Basal tumors, which do not express the androgen or estrogen receptors or HER-2, are typically associated with metastasis and often do not respond to hormonal therapies. Current treatments include chemotherapy, radiation, and surgery, but all demonstrate poor outcomes, thus highlighting the urgent need for a specific targeted therapy for the subtype.
For the study, Dr. Pestell and colleagues investigated the CCL5/CCR5 axis expression in human breast cancer cell lines and the effect of CCR5 antagonists in vitro and in vivo.
An interrogation was conducted using a microarray dataset to evaluate CCR5 and CCL5 expression in the context of 2,254 patient breast cancer samples. Samples in the dataset were assigned to five breast cancer subtypes, including luminal A, B, normal-like, basal and HER-2 overexpressing disease.
The analysis revealed an increased expression of CCL5 and CCR5 in patients with basal and HER-2 subtypes, with 58 percent indicating a positive CCR5 and CCL5 signature. The team showed that oncogenes turn on the CCR5 receptor in normal breast cells as they became transformed into cancer cells. Spread of those cells is also regulated by CCR5, they found.
To evaluate the functional relevance of CCR5 in cellular migration and invasion, the team tested the drugs in 3-D invasion assays with two different cell lines. Here, too, they discovered that both antagonists inhibited breast cancer cell invasiveness.
Next, to determine its effects in vivo, the team injected mice with the antagonists and tracked invasiveness of the basal breast cancer cells to other tissue, i.e. lung, with bioluminescence imaging. Mice treated with the drug showed a more than 90 percent reduction in both the number and size of pulmonary metastases compared to untreated mice.
“Our preclinical studies provide the rational basis for studying the use of CCR5 antagonists as new treatments to block the dissemination of basal breast cancers,” said Dr. Pestell.
These findings may also have implications for other cancers where CCR5 promotes metastasis, such as prostate and gastric.
CHICAGO— Removing a lipoprotein receptor known as SR-BI may help protect against breast cancer, as suggested by new findings presented at the American Association for Cancer Research Annual Meeting 2012 by Jefferson’s Kimmel Cancer Center researchers.
In vitro and mouse studies revealed that depletion of the SR-BI resulted in a decrease in breast cancer cell growth.
SR-BI is a receptor for high-density lipoproteins (HDL) that are commonly referred to as “good cholesterol” because they help transport cholesterol out of the arteries and back to the liver for excretion.
The team, including Christiane Danilo, of the Department Stem Cell Biology and Regenerative Medicine at Thomas Jefferson University, and Philippe G. Frank, Ph.D., an assistant professor in the Department of Stem Cell Biology and Regenerative Medicine at Jefferson, had good reason to believe that SR-BI played a role in breast cancer growth: Previous lab research had revealed that mice fed a high cholesterol diet develop more advanced tumors and their tumors produce more SR-BI.
To further investigate SR-BI’s role in breast cancer tumors, the team manipulated levels of the receptor in human breast cancer cell lines and examined its effect on tumor formation in a mouse model.
In vitro, they found that ablation of the receptor protein in breast cancer cells led to a decrease in cancer cell proliferation, migration and invasion. Mouse models also showed that depletion of the receptor could confer protection against tumor growth.
Environmental factors, such as diet and obesity, have long been considered risk factors for the high breast cancer incidence in the Western world, and epidemiologic evidence indicates that cancer patients display abnormal levels of cholesterol carrying lipoproteins. However, the role of cholesterol in breast cancer had not yet been specifically examined.
“The results of this novel study show that depletion of SR-BI reduces cancer cell and tumor growth, suggesting that it could play an important role in breast cancer,” said Dr. Frank. “More studies are warranted to further characterize the role of SR-BI in tumor progression.”
Other researchers include Michael P. Lisanti, M.D., Ph.D., Chairman of the Department of Stem Cell Biology and Regenerative Medicine at Jefferson, and Maria Antonietta Mainieri of the University of Calabria, Rende, in Italy.
The study was funded by the Susan G. Komen Foundation.
Researchers at the Kimmel Cancer Center at Jefferson have demonstrated for the first time that the metabolic biomarker MCT4 directly links clinical outcomes with a new model of tumor metabolism that has patients “feeding” their cancer cells. Their findings were published online March 15 in Cell Cycle.
To validate the prognostic value of the biomarker, a research team led by Agnieszka K. Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson, analyzed samples of patients with triple negative breast cancer, one of the most deadly of breast cancers, with fast-growing tumors that often affect younger women.
A retrospective analysis of over 180 women revealed that high levels of the biomarker MCT4, or monocarboxylate transporter 4, were strictly correlated with a loss of caveolin-1 (Cav-1), a known marker of early tumor recurrence and metastasis in several cancers, including prostate and breast.
“The whole idea is that MCT4 is a metabolic marker for a new model of tumor metabolism and that patients with this type of metabolism are feeding their cancer cells. It is lethal and resistant to current therapy,” Dr. Lisanti said. “The importance of this discovery is that MCT4, for the first time, directly links clinical outcome with tumor metabolism, allowing us to develop new more effective anti-cancer drugs.”
Analyzing the human breast cancer samples, the team found that women with high levels of stromal MCT4 and a loss of stromal Cav-1 had poorer overall survival, consistent with a higher risk for recurrence and metastasis, and treatment failure.
Applying to a Triple Threat
Today, no such markers are applied in care of triple negative breast cancer, and as a result, patients are all treated the same. Identifying patients who are at high risk of failing standard chemotherapy and poorer outcomes could help direct them sooner to clinical trials exploring new treatments, which could ultimately improve survival.
“The idea is to combine these two biomarkers, and stratify this patient population to provide better personalized cancer care,” said Dr. Witkiewicz
The findings suggest that when used in conjunction with the stromal Cav-1 biomarker, which the authors point out has been independently validated by six other groups worldwide, MCT4 can further stratify the intermediate-risk group into high and low risk.
Since MCT4 is a new druggable target, researchers also suggest that MCT4 inhibitors should be developed for treatment of aggressive breast cancers, and possibly other types. Targeting patients with an MCT4 inhibitor, or even simple antioxidants, may help treat high-risk patients, who otherwise may not respond positively to conventional treatment, the researchers suggest.
But the work stems beyond triple negative breast cancer, challenging an 85-year-old theory about cancer growth and progression.
This paper is the missing clinical proof for the paradigm shift from the “old cancer theory” to the “new cancer theory,” known as the “Reverse Warburg Effect,” said Dr. Lisanti. The new theory being that aerobic glycolysis actually takes place in tumor associated fibroblasts, and not in cancer cells, as the old theory posits.
“The results by Witkiewicz et al. have prominent conceptual and therapeutic implications,” wrote Lorenzo Galluzzi, Ph.D., Oliver Kepp, Ph.D., and Guido Kroemer, M.D., Ph.D. of the French National Institute of Health and Medical Research and Institut Gustave Roussy, in an accompanying editorial. “First, they strengthen the notion that cancer is not a cell-autonomous disease, as they unravel that alterations of the tumor stroma may constitute clinically useful biomarkers”.
“Second, they provide deep insights into a metabolic crosstalk between tumor cells and their stroma that may be targeted by a new class of anticancer agents.”
Dr. Kroemer entitled his commentary “Reverse Warburg: Straight to Cancer” to emphasize that the connective tissue cells (fibroblasts) are directly “feeding” cancer cells, giving them a clear growth and survival advantage. New personalized therapies would cut off the “fuel supply” to cancer cells, halting tumor growth and metastasis.
Takemi Tanaka, Ph.D., of Thomas Jefferson University’s School of Pharmacy and the Kimmel Cancer Center, received a $50,000 grant toward her breast cancer research, as part of the Pennsylvania Breast Cancer Coalition’s (PBCC) “Refunds for Breast and Cervical Cancer Research” initiative.
The PBCC’s grants are made possible through contributions from state taxpayers who choose to contribute all or part of their state income tax refund to the program.
Dr. Tanaka’s research focuses on breast cancer metastasis. When cancer metastasizes, cancer cells enter the distal organs through the blood vessels. Dr. Tanaka envisions those vessels as a gateway for the cells and wants to close it as tight as possible to prevent the cancer from spreading further.
Her team developed a new drug called ESTA to block the entry of breast cancer cells into the tissue. Early data show that mice treated with the drug had 60 percent less metastases without toxicity.
“I would like to express my sincere gratitude to the tax payers for their generous support for my breast cancer research to help eradicate this deadly disease,” Dr. Tanaka said. “We believe that success with our strategy may transform current breast cancer therapy and move us one step closer to a cure.”
Dr. Tanaka is one of three researchers who received funding through PBCC’s Breast and Cervical Cancer Research initiative. The other recipients are from the University of Pennsylvania and Penn State Hershey Cancer Institute.
“We’re extremely proud of Dr. Tanaka’s recognition by the Pa. Breast Cancer Coalition and thankful for the people in Pennsylvania who donated to help support these grants, as well as the PBCC for their efforts to raise awareness about breast cancer,” said Rebecca Finley, PharmD, M.S., Dean of Jefferson’s School of Pharmacy. “Dr. Tanaka’s work with this promising new drug will only help us better understand and potentially better treat this important health issue in women.”
The PBCC kicked off its annual Refunds for Breast and Cervical Cancer Research campaign to fund the cancer researchers on Monday, Feb. 13 at City Hall with Councilmen Dennis O’Brien.
Since 1997, more than $2.8 million has been donated to the Refunds for Research campaign and 71 grants have been awarded to Pennsylvania researchers looking for the cause of and cure for these common cancers in women.
Another layer in breast cancer genetics has been peeled back.
A team of researchers at Jefferson’s Kimmel Cancer Center (KCC) led by Richard G. Pestell, M.D., PhD., FACP, Director of the KCC and Chair of the Department of Cancer Biology, have shown in a study published online Feb. 6 in the Journal of Clinical Investigation that the oncogene cyclin D1 may promote a genetic breakdown known as chromosomal instability (CIN). CIN is a known, yet poorly understood culprit in tumor progression.
The researchers used various in vitro and in vivo model systems to show that elevated levels of cyclin D1 promotes CIN and correlate with CIN in the luminal B breast cancer subtype. Cyclin D1 protein is elevated in breast, prostate, lung and gastrointestinal malignancies.
The findings suggest that shifting towards drugs targeting CIN may improve outcomes for patients diagnosed with luminal B subtype. Luminal B breast cancer has high proliferation rates and is considered a high grade malignancy.
Estrogen or progesterone receptor positive and HER2 positive cancers indicate luminal B, and about 10 percent of patients are diagnosed with it every year, though many do not respond well to treatment. The identification of CIN in luminal B provides a new therapeutic opportunity for these patients.
“Cyclin D1 has a well defined role in cell proliferation through promoting DNA replication,” says Dr. Pestell. “My team was the first to discover that cyclin D1 also has alternate functions, which include regulating gene transcription at the level of DNA. We were interested in discovering the function of DNA associated cyclin D1.”
To help answer this, the researchers, including lead author Mathew C. Casimiro, Ph.D., of the Department of Cancer Biology at Thomas Jefferson University, first needed to directly access cyclin D1′s role in gene regulation.
They applied an analysis known as ChIP sequencing to study the protein’s interactions with genes that comprise the entire mouse genome, and found it occupied the regulatory region of genes governing chromosomal stability with high incidence.
They went on to show cyclin D1 promoted aneuploidy and chromosomal rearrangements typically found in cancers.
Faulty chromosomes—either too many or too few, or even ones that are the wrong shape or size—have been shown to be the crux of many cancers. However, a major question of cancer genetics is the mechanisms of CIN. What causes the breakdown in chromosomal stability?
As cyclin D1 expression is increased in the early phases of tumorigenesis, cyclin D1 may be an important inducer of CIN in tumors.
To analyze the association between CIN and cyclin D1 expression in the context of breast cancer, the team aligned an expression of a 70-gene set with the highest CIN score against over 2,000 breast cancer samples. They stratified the samples based on previously described subtypes and aligned them with cyclin D1 expression profiled across the dataset.
A significant correlation among CIN, cyclin D1 and the luminal B subtype was identified, and it was apparent that the relationship between these levels was subtype specific.
“Interestingly, previous studies have presented contradictory results,” Dr. Pestell says. “Many studies have suggested a positive correlation between cyclin D1 expression and outcomes, while others have shown reduced survival. Here, we’ve dug deep, using a genome-wide analysis, and found that overexpression of the protein appears to be directly associated with the genes involved in CIN and this correlates with the luminal B subtype.”
Drugs targeting chromosomal instability for cancer therapy have been explored, but a sub-stratification rationale for the luminal B subtype has not been established. The research presented in this study suggests such a target is worthy of further investigation.
“There is a big drive towards using targeting therapies for stratified breast cancers,” says Dr. Casimiro. “What we are thinking is that there are a growing number of drugs that target aneuploidy, like AICAR and 17-AAG, that may be used as an adjuvant therapy in patients with luminal B breast cancer.”
Researchers at the Thomas Jefferson University Hospital and Kimmel Cancer Center at Jefferson have shown that loss of the retinoblastoma tumor suppressor gene (RB) in triple negative breast cancer patients is associated with better clinical outcomes. This is a new marker to identify the subset of these patients who may respond positively to chemotherapy.
Today, no such marker is applied in care of triple negative breast cancer, and as a result, patients are all treated the same.
Agnieszka Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Erik Knudsen, Ph.D., Professor of Cancer Biology and Deputy Director of Basic Science at Jefferson’s Kimmel Cancer Center, presented the findings at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium during a poster discussion on Dec. 9.
“This is a step in trying to better direct treatment for patients with triple negative breast cancer,” Dr. Knudsen said.
In general for cancer, loss of tumor suppressor genes is associated with poor clinical outcome. However, loss of RB in triple negative breast cancer patients appears to be a predictor of favorable clinical outcomes. This is because it changes the way tumor cells respond to therapy such that they end up becoming more sensitive to chemotherapy.
The researchers retrospectively evaluated the RB status and clinical outcome of a cohort of 220 patients diagnosed and treated at Thomas Jefferson University Hospital with chemotherapy. RB loss, they found, was associated with a longer overall survival. In contrast, patients with RB had worse survival.
“Triple negative breast cancer is the most deadly of breast cancers, with fast-growing tumors, that affects younger women,” said Dr. Witkiewicz. “This work allowed us to identify a marker that could lead to better treatment for patients. It’s about female personalized medicine.”
Edith Mitchell, M.D., Professor of Medical Oncology at Jefferson, and Adam Ertel, Ph.D., a research instructor in the Department of Cancer Biology, were also involved in the study.
The next step for the researchers is a clinical trial at Jefferson to confirm their findings. Tumors of newly-diagnosed patients with triple negative breast cancer will be tested for the RB gene before they receive chemotherapy. After treatment, the data will be evaluated to determine the efficacy of directing future patient care.
This study represents one important example of personalized medicine being performed at the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University and the Kimmel Cancer Center to improve patient care.
Gordon F. Schwartz, MD, MBA, FACS, director of the Jefferson Breast Care Center, will represent the American Society of Breast Disease on the board of the National Accreditation Program for Breast Centers (NAPBC).
The NAPBC is a consortium of national, professional organizations dedicated to the improvement of the quality of care and the monitoring of outcomes for patients with diseases of the breast.
Dr. Schwartz attended his first meeting as a member of the board in San Francisco the week of October 24 during the 2011 Clinical Congress of the American College of Surgeons.
Dr. Schwartz is an internationally renowned expert in breast diseases and a professor of surgery and medical oncology at Thomas Jefferson University Hospital. His practice has been dedicated to treating breast diseases, both benign and malignant, for more than 30 years.
In 2009, Dr. Schwartz became director of the Jefferson Breast Care Center—one of the first Academic Medical Institutions receiving full accreditation by NAPBC.
From October forward, the Kimmel Cancer Center at Jefferson (KCC), a National Cancer Institute-designated cancer center, is celebrating 20 years of service to the community and the groundbreaking cancer research from the scientists and physicians who’ve provided an invaluable contribution to medical science and healthcare.
“This is truly a milestone for the Kimmel Cancer Center—it’s two decades of caring and collaborating to beat cancer,” says Richard Pestell, M.D., Ph.D., director of the KCC and Chair of the Department of Cancer Biology at Thomas Jefferson University.
“With our multidisciplinary approach, KCC’s team of clinicians and researchers has continued to put their best feet forward to provide excellent, stand-out personalized care for cancer patients in the Philadelphia region and beyond and uncover new pathways to better prevent, diagnose and treat the disease,” he added.
Today, the KCC offers up an experienced team of medical and radiation oncologists, surgeons, pathologists, urologists, neurosurgeons, nurses and other specialists for patients as they fight against cancer. With the Jefferson Breast Care Center, the Bodine Center for Radiation Therapy, the Myrna Brind Center of Integrative Medicine, and Jefferson Pancreatic, Biliary Tract and Related Cancer Center, to name a few, patients have access to the best facilities, providers and technologies for cancer screening and treatment.
It was October 1991 when the Jefferson Cancer Institute opened, with the dedication of the Bluemle Life Science Building on the Thomas Jefferson University campus. Four years later, with the awarding of a Cancer Center Support Grant, the National Institutes of Health National Cancer Institute (NCI) officially recognized it as one of only 54 NCI-designated cancer centers in the U.S. at the time. The institute took its current name in 1996 when businessman and philanthropist Sidney Kimmel made a generous donation to the institute to expand its research activities.
The donation to Jefferson is not a “gift,” but “an investment for humanity,” Mr. Kimmel told the Philadelphia Inquirer in 1996. “I really believe we’re going to have a breakthrough” in cancer research.
Living up to his expectations, KCC cancer researchers have made significant contributions over the last two decades, including better care in prostate cancer (Leonard Gomella, M.D.); new targets and diagnostics for prostate and breast cancer (Hallgeir Rui, M.D., Ph.D., Dr. Pestell); discoveries in colon cancer (Scott Waldman, M.D., Ph.D); pioneering discoveries in cancer metabolism and stem cells (Michael Lisanti, M.D. Ph.D., Dr. Pestell); better bone marrow transplants (Neal Flomenberg, M.D.); more selective radiation treatment (Adam Dicker, M.D.); and new areas of the human genome to treat (Isidore Rigoutsos, Ph.D., and Paolo M. Fortina, M.D., Ph.D.).
Dr. Pestell, who became director in 2005, has made significant contributions to understanding cell cycle regulation and the aberrations that can lead to cells turning cancerous. His work identified new molecular markers, and new targets for cancer treatment. An internationally renowned expert in oncology and endocrinology, Dr. Pestell’s record of research funding is outstanding, securing substantial National Institutes of Health grants for the KCC.
Today, KCC’s well-funded basic science programs include cell biology, immunology and structural biology, developmental therapeutics, melanoma, leukemia/lymphoma, prostate and breast cancers, and gastrointestinal and genitourinary cancers. KCC also conducts numerous cancer clinical trials each year aimed at prevention and treatment of cancer.
Two recent clinical trials have resulted in the addition of new procedures at Thomas Jefferson University Hospital. For example, in the Department of Urology, under chairman Leonard Gomella, M.D, a bladder cancer diagnostic tool using an imaging agent and blue light technology is now helping physicians better detect tumors along the bladder lining. Also, a new, two-step approach to half-match bone marrow transplants (where a patient can use a sibling or parent as a donor) developed by Chair of Medical Oncology Neal Flomenberg, M.D., is proving to be a success for blood cancer patients whose options were otherwise limited. Jefferson is the only hospital in the region performing half-match procedures.
Since being appointed as chair of the Department of Radiation Oncology in 2010, Adam Dicker, M.D., Ph.D., has led extensive clinic renovations and the ongoing addition of new technologies. That includes Bodine’s recently acquired radiation therapy equipment for head and neck and prostate cancer patients and an upcoming radiosurgey instrument designed to deliver higher doses of radiation to smaller areas. Bodine’s state-of-the-art brachytherapy suite is also set to open in early 2012.
Last year, Charles J. Yeo, M.D., Chair of Surgery, performed his 1,000th Whipple procedure. The Whipple procedure is a major surgical operation involving removal of portions of the pancreas, bile duct and duodenum, and is typically performed to treat malignant tumors involving the pancreas, common bile duct or duodenum. Jefferson’s surgery department treats more pancreatic cases than anywhere in the region.
Thomas Jefferson University Hospital is consistently ranked in the top 50 best hospitals for treating cancer in America (#31 in 2011) in U.S. News and World Report. What’s more, the hospital has moved up more than 20 places in the past five years for cancer.
Taking a leukemia chemotherapy drug may help breast cancer patients who don’t respond to tamoxifen overcome resistance to the widely-used drug, new research from the Kimmel Cancer Center at Jefferson suggests.
Interestingly, researchers found that tamoxifen combined with dasatinib, a protein-tyrosine kinase inhibitor, reverses the chemo-resistance caused by cancer-associated fibroblasts in the surrounding tissue by normalizing glucose intake and reducing mitochondrial oxidative stress, the process that fuels the cancer cells.
Previous animal studies have confirmed that combining tyrosine kinase inhibitors with anti-estrogen therapies, like tamoxifen, can prevent drug resistance, but none have suggested that the target of the inhibitors is the cancer-associated fibroblasts.
The researchers report their findings in the August 1 issue of Cell Cycle.
About 70 percent of women diagnosed with breast cancer will have estrogen receptor positive (ER(+)) disease, which indicates that the tumor may respond to tamoxifen. However, a large percentage of these tumors—up to 35 percent—have little to no response to the drug or eventually develop resistance to it.
In this study, researchers sought to better understand drug resistance by looking at the metabolic basis in an ER (+) cell line and cancer-associated fibroblasts. The researchers have previously established a relationship between the two, where cancer cells induce aerobic glycolysis by secreting hydrogen peroxide in adjacent fibroblasts via oxidative stress. In turn, these fibroblasts provide nutrients to the cancer cells to proliferate, a process that ultimately makes tumors grow.
Here, they investigated and then demonstrated that this interaction was also the basis of tamoxifen resistance.
In a sense, the drug combination had an “antioxidant effect” in these types of cancer cells, according to Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center.
“The fibroblasts are what make ER (+) cancer cells resistant to the tamoxifen,” said Dr. Lisanti. “But the tamoxifen plus dasatinib maintained both fibroblasts and cancer cells in a ‘glycolytic state,’ with minimal oxidative stress and more cell death, most likely because of an absence of metabolic coupling. The supply between the two was cut.”
“This suggests resistance to chemotherapeutic agents is a metabolic and stromal phenomenal,” he added.
Researchers showed that ER (+) cancer cells alone responded to tamoxifen but when co-cultured with human fibroblasts had little to no effect. Similarly, dasatinib, a chemotherapy drug used to treat leukemia patients who can no longer benefit from other medications, had no effect on fibroblasts alone or cancer cells. Together, however, the drugs prevented the cancer cells co-cultured with the fibroblasts from using high-energy nutrients from the fibroblasts.
This combination resulted in nearly 80 percent cell death, the team reported—a two to three fold increase when compared with tamoxifen alone.
“The drugs have no effect when they are used alone—it’s in unison when they effectively kill the cancer cells in the presence of fibroblasts,” said Dr. Lisanti. “This opens up the door for possible new treatment strategies. This ‘synthetic lethality’ may help patients overcome resistance in the clinic.”
Researchers involved in the study include Ubaldo E. Martinez-Outschoorn, of the Jefferson Stem Cell Biology and Regenerative Medicine Center and Department of Medical Oncology; Zhao Lin, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology;Ying-Hui Ko, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology; Allison F. Goldberg, of the Department of Surgery; Neal Flomenberg, chair of the Department of Medical Oncology; Chenguang Wang, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology; Stephanos Pavlides, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology; Richard G. Pestell, director of the Kimmel Cancer Center at Jefferson and Chair of the Department of Cancer Biology; Anthony Howell, of the Manchester Breast Centre & Breakthrough Breast Cancer Research Unit; and Federica Sotgia, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology.