KCC Researchers Awarded $480,000 from Breast Cancer Research Foundation

Richard Pestell, MD, PhD and Andrew Quong, PhD

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.



Researchers Discover Molecule That Drives Aggressive Breast Cancer

Richard G. Pestell, M.D., Ph.D.

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, jackie.kozloski@jefferson.edu.



Breast Cancer Patients Who Lack RB Gene Respond Better to Neoadjuvant Chemotherapy

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).



HIV Drug May Slow Down Metastatic Triple-Negative Breast Cancer

Richard Pestell, M.D., Ph.D, Director of the KCC

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.

Recent articles about this discovery have also appeared in NewsWise and the Philadelphia Inquirer.




HIV drug may slow down metastatic breast cancer

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.



AACR: Eliminating the ‘Good Cholesterol’ Receptor May Fight Breast Cancer

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.



Taxpayers Give Back for Cancer: Jefferson Researcher Awarded ‘Refunds for Research’ Grant

Takemi Tanaka, Ph.D., of Thomas Jefferson University’s School of Pharmacy and the Kimmel Cancer Center

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.

From the left: Ashiwel Undieh, Chair of Pharmaceutical Sciences, Pat Halpin-Murphy, founder of PBCC, Dr. Tanaka, and Rebecca Finley, Dean of the Jefferson School of Pharmacy

“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.



Drugs targeting chromosomal instability may fight a particular breast cancer subtype

Richard Pestell, M.D., Ph.D, Director of the KCC

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.”



‘A Welcome New Addition’ to Field: Dr. Juan Palazzo Authors Breast Pathology Book

Juan P. Palazzo, M.D., an anatomic/surgical pathologist at Thomas Jefferson University Hospital and the Jefferson Breast Care Center, has authored a book that tackles the hard cases in breast disease pathology faced by many clinicians in the healthcare world today.

According to Amazon, Difficult Diagnoses in Breast Pathology (Demos Medical) provides a highly visual presentation of the major problems and questions that a pathologist is likely to encounter in the evaluation of common and uncommon breast diseases.

Addressing real-world diagnostic problems faced in daily practice, the book includes needle core biopsy interpretation, diagnosis of precursor lesions, early stage disease, and recognition of neoplastic mimics and other misleading variants.

Each chapter is authored by a recognizePathologist Dr. Juan P. Palazzod expert in the area, and includes hundreds of high-quality images.

“This is a welcome new addition to this field and it delivers with concise, clear writing, ample illustrations, and appropriate comments on ancillary techniques. This latest addition to the field of histomorphology of (surgical) breast disease compares favorably with many more extensive books,” writes Doody’s Reviews.

Dr. Palazzo is pathologist with over 25 years experience and has been named a U.S. News & World Report “Top Doctor.”

The book is available here.



Gordon Schwartz, M.D., Nominated to National Accreditation Program for Breast Centers Board

Gordon F. Schwartz, MD, MBA, FACS, director of the Jefferson Breast Care Center

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.



Jefferson-Eagles Breast Health Floor Dedication Event

Ribbon Cutting at Jefferson Breast Care Center for Eagles floor and donor wall: Dr. Richard Pestell, director of KCC, Caity Buck, breast cancer survivor, Eagles owner Christina Lurie, Eagles safety Kurt Coleman, and Tom Lewis, president & CEO of TJUH

On October 11, the Jefferson Breast Care Center unveiled the Jefferson-Philadelphia Eagles Breast Health floor with a ribbon-cutting ceremony.

The speakers were Jefferson President and CEO Tom Lewis, Director of the Kimmel Cancer Center at Jefferson Dr. Richard Pestell, Eagles owner Christina Lurie, Eagles safety Kurt Coleman and breast cancer survivor Caity Buck.

Earlier this year, renovations were completed on the 3rd floor of the Jefferson Breast Care Center, thanks to the $1.04 million raised through the Philadelphia Eagles’ “Tackling Breast Cancer” campaign. Because of the team, its fans and partners, Jefferson patients can now benefit from a true multidisciplinary clinical team in this newly renovated space.

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.

Fox 29 and Comcast SportsNet covered the dedication event.



Jefferson Researchers Unlock Key to Personalized Cancer Medicine Using Tumor Metabolism

Identifying gene mutations in cancer patients to predict clinical outcome has been the cornerstone of cancer research for nearly three decades, but now researchers at the Kimmel Cancer Center at Jefferson have invented a new approach that instead links cancer cell metabolism with poor clinical outcome. This approach can now be applied to virtually any type of human cancer cell.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center at Jefferson

The researchers demonstrate that recurrence, metastasis, and poor clinical outcome in breast cancer patients can be identified by simply gene profiling cancer cells that are using ketones and lactate as a food supply.

These findings are reported in the April 15th online issue of Cell Cycle. The investigators are calling this new approach to personalized cancer medicine “Metabolo-Genomics.”

High-energy metabolites have long been suspected to “fuel” aggressive tumor cell behavior. The researchers used this premise to generate a gene expression signature from genetically identical cancer cells, but one cell group was fed a diet of high-energy metabolites. These lactate- and ketone-induced “gene signatures” then predicted recurrence, metastasis, and poor survival.

So, it appears that what cancer cells are eating determines clinical outcome, not necessarily new gene mutations.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center at Jefferson, together with other researchers,  found that treatment of human breast cancer cells with high-energy metabolites increases the expression of genes associated with normal stem cells,  including genes upregulated in embryonic and neural stem cells.

What’s more, lactate and ketones were found to promote the growth of normal stem cells, which has critical applications for stem cell transplantation and for a host of different human diseases.  It appears that these metabolites increase “stemness” in cancer cells, which drives poorer outcomes.

“Tumors that are using the body’s own nutrients (lactate and ketones) as “fuel” have a poorer outcome for patient survival, a behavior that now can be used to predict if a patient is at a high-risk for recurrence or metastasis,” Dr. Lisanti said. “This is getting to the heart of personalized cancer medicine. Now, we have identified a panel of biomarkers that directly links cancer metabolism with targeted cancer therapy.”

These findings suggest, according to the authors, that high-risk cancer patients (those whose cancer cells use high-energy metabolites) can be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the antioxidant metformin, a drug that is also used to treat diabetes.

“Knowing the gene signatures of patients whose cancer cells are “eating” these metabolites for fuel is a pivotal piece of new information that we can use to diagnose and treat cancer patients,” said Martinez-Outschoorn, M.D., of the department of Medical Oncology at Thomas Jefferson University, and the lead author of the paper. “It’s not just that we know those patients will have poor survival; we know that those patients are using mitochondrial metabolism, which is the type of energy metabolism that we should be targeting with new anti-cancer drugs.”

The researchers propose that this new approach to diagnosis and subsequent treatment be called “Metabolo-Genomics” since it incorporates both cell metabolism and gene transcriptional profiling. This strategy could now be used to direct which patients receive a particular “tailored” anti-metabolic therapy.

Genetic markers, like expression of the mutationally activated HER2 gene, provide biomarkers that can be used to identify breast cancer patients at high-risk for recurrence or metastasis, and to modify their subsequent treatment with targeted therapies (i.e., herceptin, a drug used in aggressive breast cancers).  But with “Metabolo-Genomics,” it is now about using “global” cancer cell metabolism for these predictions.

“Just by feeding cancer cells a particular energy-rich diet, it changes their character, without introducing mutations or altering their genetic profile,” Dr. Lisanti said.  “We’ve only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile.  It’s a new biomarker for “lethal” cancers that we can now treat with the right drugs, such as the antioxidant metformin.

Dr. Lisanti and his colleagues believe that tumor metabolism is the new big picture for understanding how cancers undergo recurrence and metastasis.