How Aging Normal Cells Fuel Tumor Growth and Metastasis

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.

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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.

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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.

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Key References:  Capparelli et al.

http://www.landesbioscience.com/journals/cc/article/20717/

http://www.landesbioscience.com/journals/cc/article/20718/

http://www.landesbioscience.com/journals/cc/article/20920/

http://www.landesbioscience.com/journals/cc/article/20964/

Also see:

http://tumor-microenvironment.com/

http://www.cancer.gov/newscenter/pressreleases/2011/ThosJeffersonUStudyofTamoxifenResistance

http://blog.kimmelcancercenter.org/?p=2773
http://physics.cancer.gov/news/2011/march/po_news_a.asp
http://physics.cancer.gov/news/2011/may/po_news_a.asp

http://physics.cancer.gov/news/2011/june/po_news_e.asp

http://physics.cancer.gov/news/2011/june/sept/po_news_d.asp
http://physics.cancer.gov/news/2011/sept/po_news_d.asp
http://physics.cancer.gov/news/2012/jan/po_news_f.asp
http://physics.cancer.gov/news/2012/feb/po_news_e.asp



Kimmel Cancer Center at Jefferson Hosts a Patient Symposium Focusing on Melanoma of the Eye

The Kimmel Cancer Center will host the inaugural Eyes on a Cure: Patient and Caregiver Symposium”  on June 16 and 17.

The symposium will bring uveal melanoma patients, caregivers, and researchers from around the world together to offer educational sessions, support groups led by oncology social workers, sessions on complementary therapies, as well as informal time for networking.

Uveal melanoma, also known as ocular melanoma (OM), is diagnosed in about 2,000 people a year in this country. Though rare, it is the most common eye cancer in adults.

The Community United for Research and Education of Ocular Melanoma, or CURE OM, was created by the Melanoma Research Foundation (MRF).

Over 100 patients, along with their families, are expected to attend the event.

The Kimmel Cancer Center at Jefferson is a major center for the treatment of OM. Medical oncologist Takami Sato, MD, PhD, one of the leading specialists in the disease,has seen more than 100 new patients with metastatic uveal melanoma every year since 1999.

David Eschelman, MD, and Carin F. Gonsalves, MD of the Division of Cardio-Interventional Radiology at Jefferson, have performed more than 300 embolization procedures for the liver metastases from uveal melanoma last year.

And the Jefferson team works closely with Jerry Shields, M., and Carol Shields, MD, of Wills Eye Institute in Philadelphia, who see more than 500 patients with primary uveal melanoma every year.

All are scheduled to speak over the course of the two days.

“Not many patients know about the disease and many have struggled with finding an appropriate treatment,” says Dr. Sato. “This is an opportunity to educate, as well as provide patients with support from both social workers and doctors—and hopefully foster research collaborations and funding opportunities. We are very honored to be hosting it.”

Director of CURE OM Sara Selig, Timothy Turnham, Ph.D., the Executive Director of the Melanoma Research Foundation, Daniel Brown, MD, of the Department of Interventional Radiology, and Rani Anne, M.D., of the Department of Radiation Oncology will also speak.

To learn more about the CURE OM Conference at the Kimmel Cancer Center click here.

To read the blog post about Sara Selig and her husband’s battle with OM and their efforts to bring more attention to the disease, click here.



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.




Jefferson Kimmel Cancer Center Tribute Dinner Honoring Steve Sabol, President of NFL Films

On Tuesday, June 5, 2012, the Kimmel Cancer Center at Jefferson and 300 guests honored Steve Sabol, President for NFL Films benefiting cancer research and patient care at the Union League of Philadelphia. The evening’s remarks were delivered by Sidney and Caroline Kimmel; and NFL Films special guests, Greg Cosell, and Pat Kelleher. Also in attendance was Head Coach for the Philadelphia Eagles, Andy Reid and his wife, Tammy; along with other key members of the Eagles organization. The silent auction, which featured an original art piece by Steve Sabol entitled, “Hippocratic Oath” as well as a private tour of NFL Films was emceed by Philadelphia’s own, “The Geator with The Heater”, Jerry Blavat.

Dr. Richard Pestell, Director of the Kimmel Cancer Center, presented Steve Sabol with the Spirit of Courage Award, presented to an individual who has demonstrated great personal courage, strength and dignity while battling cancer and supporting others in their fight against cancer. Receiving the Spirit of Commitment Award was Roberta Tanenbaum, Kimmel Cancer Center Advisory Board member, and Joseph Weiss, Kimmel Cancer Center Advisory Board Member and Chairman of Electronic Ink, presented to an individual to recognize outstanding commitment to supporting the work of the Kimmel Cancer Center through personal and professional contributions dedicated to finding a cure.

The Lead Sponsor was the Sidney Kimmel Foundation. Kimmel Cancer Center at Thomas Jefferson University and Hospitals would also like to thank our generous Sponsors and Committee:

Program (13 MB PDF)

Chairpersons

Roberta Tanenbaum
KCC Board Member

Joseph Weiss
KCC Advisory Board Member
Chairman, Electronic Ink

Honorary Co-chairpersons

Anne and Matt Hamilton

Co-chairpersons

Dorothy and David Binswanger
Linda Golden and Richard Davidson
Linda and Benjamin Frankel
Janis and Stephen Goodman
Caroline and Sidney Kimmel
Christina and Jeffrey Lurie
Nataliia and Richard Pestell
Judy and Marvin Rounick
Kathy and John Spagnola

Committee

Ken Adelberg
Betty Gross Eisenberg
Stephen Foxman
Judy Losben
Linda Massey
Al Pizzica
Rita Rome
Claire Rose
Wendy Voron
Renee Zuritsky



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.



ASCO: Younger Colon Cancer Patients Have Worse Prognosis at Diagnosis, Yet Better Survival

Younger patients with colorectal cancer were more likely to present advanced stage tumors at diagnosis and metastasize much sooner, yet had better than or equal survival to patients 50 and older, according to data being presented at the 2012 American Society of Clinical Oncology Annual Meeting in Chicago. (Abstract #3621, Monday, June 4, 8:00 AM – 12:00 PM CST, S Hall A2).

The study was led by Edith Mitchell, M.D., a clinical professor in the Department of Medical Oncology at Jefferson Medical College of Thomas Jefferson University. Dr. Mitchell is also Director of the newly-established Center to Eliminate Cancer Disparities at Jefferson’s Kimmel Cancer Center.

“We’re seeing more advanced tumors in this population because the cases aren’t being caught early enough,” said Dr. Mitchell. “Screening isn’t recommended until age 50, and the younger a patient is, the more likely they are to ignore symptoms of more advanced stages of the disease.”

The objective of this study was to assess pathological features and outcomes of colorectal cancer in patients less than age 50 using an institutional sample and comparing to the Surveillance, Epidemiology and End Results (SEER) database.

Dr. Mitchell and colleagues obtained data from the tumor registry of Thomas Jefferson University Hospital (TJUH) on 4,595 patients treated for colorectal cancer from 1988 to 2007. They compared those data with data obtained from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database on 290,338 patients with colorectal cancer treated from 1988 to 2004. The researchers collected data on location, stage and histologic grade of the cancer.

Patients under age 50 with colorectal cancer presented with more advanced stage tumors in both data sets (SEER and TJUH), and had more poorly differentiated tumors than older patients, the researchers found. Patients under 50 also had more mucinous/signet ring cell tumors with 12 percent to 8.1 percent in the TJUH data and 13.2 percent to 10.3 percent in the SEER data, with younger males having the highest prevalence in both data sets.

Younger patients had fewer right-side tumors than patients 50 and over, and a higher proportion of rectal tumors. Patients under age 50 were also more likely to have positive nodes at all stages relative to 50 and over, as well as more likely to develop peritoneal metastases, but less likely to have lung metastases than older patients.

Despite their poor pathologic features, patients under age 50 had better than or equal survival to those 50 and older, which may in part be explained by their overall health. Early evidence suggests that younger patients are able to tolerate more aggressive cancer therapies because of fewer co-morbidities, said co-author Scott Goldstein, M.D., of Jefferson’s Department of Surgery.

“Ongoing studies will help clarify the survival disparity and assess differences in treatment and molecular features between younger and older colorectal cancer patients,” Dr. Mitchell said.

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Other researchers included Allan Topham, Pramila R. Anne, of Jefferson’s Department of Radiation Oncology, Gerald Isenberg, M.D., of Jefferson’s Department of Surgery, Fran Guiles of Jefferson’s Oncology Data Services, and Juan Palazzo, M.D., of Jefferson’s Department of Pathology, Anatomy and Cell Biology.

Also see: Thomas Jefferson University Hospital Oncologists and Surgeons Treating More Colon Cancer Patients Under 50



ASCO: Liver Metastases and its Prognostic Significance in Men With Metastatic Castration-Refractory Prostate Cancer

Liver metastases predicts shorter overall survival in men with metastatic castration-refractory prostate cancer (mCRPC), according to data being presented at the 2012 American Society of Clinical Oncology Annual Meeting in Chicago. (Abstract # 4655, Sunday, June 3, 8:00 AM – 12:00 PM CST, S Hall A2).

In a phase III trial, lead study author William Kevin Kelly, DO, Thomas Jefferson University Hospital and the Kimmel Cancer Center at Jefferson, and colleagues from the Alliance for Clinical Trials in Oncology, found that men without liver metastases lived 8.2 months longer compared to men whose cancer did metastasize, despite both groups having similar progression free survival and response to docetaxel based chemotherapy.

The multi-institutional study included 1,050 patients from the CALGB 90401 trial, a randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with mCRPC.

For the investigation, researchers assessed the prognostic significance of liver metastases in predicting overall survival and progression free survival, adjusting for stratification factors.

Fifty-nine (5.6%) of those patients had documented liver metastases.  Patients with liver metastases had higher baseline alkaline phosphatase (ALK) and lactate dehydrogenase (ADH) levels compared to patients without liver metastases. The median overall survival time in patients with liver metastases was 14.4 compared to 22.6 months for patients without liver metastasis(hazard ratio (HR) 1.4) . The HR for treatment effect (docetaxel and prednisone with either bevacizumab or placebo) for liver metastases was not statistically significant for either group.

The full abstract can be found here. http://abstract.asco.org/AbstView_114_96038.html



Data Continues to Support Provenge’s Overall Survival Benefit in Prostate Cancer Patients

This article was adapted from an OncLive story posted on May 21, 2012.

Leonard G. Gomella, M.D, chair of the Department of Urology at Thomas Jefferson University Hospital and director of Clinical Affairs, Jefferson’s Kimmel Cancer Center, was part of the team to present new findings from the IMPACT trial looking at the immunotherapy sipuleucel-T (Provenge) in men with advanced prostate cancer.

The abstract was presented at the American Urological Association (AUA) Annual Meeting in Atlanta.

Results from the exploratory, multi-institutional analysis provides important insight into how the cross-over design of the IMPACT trial may have affected the overall survival findings, and supports a greater treatment effect of sipuleucel-T than previously reported.

In the study,  researchers administered the vaccine APC8015F to a group of patients from the control arm of three randomized, Phase 3 clinical trials evaluating sipuleucel-T, a similar, FDA-approved cancer vaccine for metastatic castrate resistant prostate cancer.

APC8015F is made from immune system cells taken from a patient with prostate cancer; however, unlike sipuleucel-T, which is never frozen, APC8015F is cryopreserved at a time before the disease progressed.

Of the 249 men in the control arm, 155 received APC8015F. Those receiving APC8015F demonstrated similar benefits to those receiving sipuleucel-T. However, these patients were grouped with the placebo arm, when the benefits were calculated.

Removing the patients that received APC8015F and comparing just the patients that received placebo alone to those receiving sipuleucel-T alone more than doubles the 4.1-month median survival benefit found in the IMPACT trial.

“From my viewpoint, the benefit of sipuleucel-T has been understated because many of the patients who received the frozen product on the control actually enjoyed a longer survival, decreasing the difference between the control arm and the treatment arm,” Dr. Gomella tells OncLive.

“In fact, if you look at our analysis of the patients who received the frozen product on the control arm and those that did not receive it, there was a significant survival advantage to those patients who did receive the frozen product. So it actually made a difference between the control arm and treatment arm much closer. And if you actually take those patients out who did not receive the frozen product on the control arm, that survival difference actually approaches 10 to 11 months.”

Watch the full interview here: http://www.onclive.com/onclive-tv/Dr-Gomella-on-the-IMPACT-Trial-Survival-Benefit

Source: OncLive



Jefferson’s Kimmel Cancer Center to Host Tribute Dinner Honoring Steve Sabol, President of NFL Films

Steve Sabol

Jefferson’s Kimmel Cancer Center will host a tribute dinner to honor legendary filmmaker Steve Sabol, President of NFL Films, with the Spirit of Courage Award at the Union League of Philadelphia on June 5.

The award is presented to an individual who has demonstrated great personal courage, strength and dignity while battling cancer and supporting others in their fight against cancer.

Since being diagnosed with brain cancer in March of 2011, Mr. Sabol, who is currently being treated at the Kimmel Cancer Center, has helped people understand the impact of this disease, all while acting as a role model of perseverance.

“It’s an honor to be recognized by the Kimmel Cancer Center at Jefferson with this award, and, more importantly, to be part of what will be a memorable event recognizing the importance of advancing clinical care and cancer research,” said Mr. Sabol. “Because of Jefferson’s treatment and Dr. Kevin Judy of the Jefferson Hospital for Neuroscience, I’ve been able to move forward through this battle. I thank everyone at the KCC for that and for the support of everyone attending the event.”

Sidney and Caroline Kimmel will be attending the event to honor Mr. Sabol, with Mrs. Kimmel giving some introductory remarks. Richard Pestell, M.D., Ph.D., FACP, Director of Jefferson’s Kimmel Cancer Center, will present the Spirit of Courage award.

Mr. Sabol is best known as President of Mt. Laurel-based NFL Films, which was founded by his father, Ed Sabol, who was recently inducted into the Football Hall of Fame.  Steve Sabol is recognized for having revolutionized not only how we watch football, but also the very nature of sports broadcasting. While NFL Films has won over 100 Emmys, Sabol himself has received 35 of those Emmys for writing, cinematography, editing, directing, and producing.

No one else in all of television has earned as many Emmys in as many different categories.

Mr. Sabol will also be donating one of his trademark pieces of art for the event for live auction.

His collage art is a natural outgrowth of his cinematic vision.  Mr. Sabol has spent his entire career thinking about football and the positive values the game represents.  In the process, football became a prism for looking at American society.  Using symbolic imagery from both the sports world and popular culture, Mr. Sabol has created a unique visual language that hearkens to times past and reminds us of the best in ourselves.

The auctioned artwork and event will benefit cancer research at Jefferson’s Kimmel Cancer Center.

“This is a very special award to the Kimmel Cancer Center because it honors those rare individuals whose courage and dignity have stood out,” said Dr. Pestell. “It’s with great pleasure to give the Spirit of Courage award to Mr. Sabol, who has no doubt inspired and empowered others—throughout his career and his fight against cancer.”

Chairpersons include Roberta Tanenbaum and Joseph Weiss, along with Honorary Co-Chairpersons Anne and Matt Hamilton.

Co-chairpersons include: Dorothy and David Binswanger, Linda Golden and Richard Davidson, Linda and Benjamin Frankel, Janis and Stephen Goodman, Caroline and Sidney Kimmel, Christina and Jeffery Lurie, Nataliia and Richard Pestell, Judy and Marvin Rounick, and Kathy and John Spagnola.

For more information, please contact Mika Harding, Associate Director for Development, Kimmel Cancer Center, 215-503-1195, Mika.Harding@KimmelCancerCenter.Org, or visit http://www.kimmelcancercenter.org/about/tribute-dinner.html



Jefferson Receives $2.6 Million NIH Grant to Study Imaging Method to Stage Prostate Cancer Without Biopsy

Mathew Thakur, PhD, professor of Radiology at Jefferson Medical College of Thomas Jefferson University and the Director of the Laboratories of Radiopharmaceutical Research and Molecular Imaging

Jefferson’s Kimmel Cancer Center and the Department of Radiology at Thomas Jefferson University received a five-year, $2.6 million grant from the National Institutes of Health (NIH) to investigate a potentially revolutionary method that can stage prostate cancers and detect recurrent disease so accurately, it would significantly reduce the number of confirmation biopsies. Such biopsies can be invasive, costly, and often lead to false-positive readings.

The new technique involves the use of a positron emission tomography (PET) scan and a novel imaging agent.

The study is being led by Mathew Thakur, PhD, professor of Radiology at Jefferson Medical College of Thomas Jefferson University and the Director of the Laboratories of Radiopharmaceutical Research and Molecular Imaging.

Prostate specific antigen (PSA) measurements, ultrasonography and magnetic resonance imaging (MRI) remain standard tools for diagnosis and management of prostate cancer; however, each requires an invasive biopsy for histologic confirmation.

Biopsies are associated with morbidity and high costs, and more than 65 percent of the 1.5 million biopsies performed each year in the U.S. show benign pathology, indicating a high false-positive rate for these standard diagnostic tools.

These limitations, the researchers say, demonstrate a dire need for noninvasive methods that can accurately stage prostate cancer, detect recurrent disease and image metastatic lesions with improved reliability.

Dr. Thakur and colleagues are studying Cu-64 peptide biomolecules to evaluate prostate cancer tumors via PET imaging. These agents detect prostate cancer by finding a biomarker called VPAC1, which is overexpressed as the tumor develops.

“The challenge has been to develop an imaging agent that will target a specific, fingerprint biomarker that visualizes prostate cancer early and reliably,” said Dr. Thakur, who is also a member of Jefferson’s Kimmel Cancer Center.

Previous studies with Cu-64 peptides from Dr. Thakur yielded promising results in stratifying breast cancer.  A preclinical study published in the Journal of Nuclear Medicine in late 2009 found that 64Cu-TP3805 detected tumors overexpressing the VPAC1 oncogene more accurately in mice than 18F-FDG, a commonly used agent for imaging tumors.

With this NIH grant, the researchers will test the hypothesis in both mice and humans.  They will evaluate two Cu-64 peptides specific for VPAC1 in mice and perform a feasibility study in 25 pre-operative prostate cancer patients, using the best suited Cu-64 peptide determined from the mouse studies.

“This noninvasive method could significantly contribute to the management of prostate cancer,” said Dr. Thakur. “It would result in a reduction of unnecessary biopsy procedures and under treatment or over treatment that yield minimal benefits, incontinence, or impotence.”

Other researchers include Ethan Halpern, MD, Charles Intenzo, MD, and Sung Kim, MD of the Department of Radiology, Edouard Trabulsi, MD of the Department of Urology and Eric Wickstrom, PhD, of the Department of Biochemistry and Molecular Biology. The team will partner with NuView, a molecular imaging technology firm, on the study.

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This study was funded by NIH’s National Cancer Institute (Grant No. 1R01CA157372-01A)



A Closer Look at PARP-1 Reveals Potential New Drug Targets

John M. Pascal, Ph.D., an assistant professor in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University

A new study published in Science May 11 is shedding light on the molecular details of PARP-1, a DNA damage-detecting enzyme that when inhibited has been shown to be effective in fighting cancer and other diseases.

The investigation led by John M. Pascal, Ph.D., an assistant professor in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University and Jefferson’s Kimmel Cancer Center, revealed new target sites—including specialized “zinc finger” domains—for drugs aiming to stop PARP-1 activity.

The idea for this area of research is to identify more specific PARP-1 inhibitors that achieve a targeted inhibition, with less potential for side effects.  Drugs inhibiting PARP-1 have also been proven effective in treating inflammation and cardiac disease.

“PARP-1 has been identified as a valuable target, but what’s special about it? What really are its weak points in the way it gets activated?” said Dr. Pascal. “We wanted to define a structural and mechanistic framework to better understand how to specifically inhibit PARP-1.”

The weak points were found to be multi-domain interfaces that are uniquely found in PARP-1.  What researchers now know is that multiple domains of PARP-1 come together and bind to DNA damage, and this “communication” between domains is essential for DNA damage-dependent PARP-1 activity.

PARP-1 is a protein that detects and responds to breaks in the structure of DNA, a potentially lethal form of damage to our genetic information. If PARP-1 activity is impaired, DNA strand breaks are not repaired and instead are converted into more dangerous types of DNA damage.  In normal tissue, a repair mechanism called homologous recombination picks up the slack and fixes the damaged DNA. However, in cancers that carry the BRCA mutation, like certain breast and ovarian cancers, homologous recombination is inactivated.  Therefore, the cancerous cells have become dependent on the role PARP-1 plays in DNA repair.

In a more general scenario, inhibiting PARP-1 has been successful when combined with DNA-damaging drugs because it heightens the apoptotic activity of these drugs. In other words, it helps halt tumor growth.

Today, many PARP-1 inhibitors being tested in preclinical and clinical studies target the catalytic active site.  But this approach is limiting because the catalytic site is similar to those found in other PARP-like proteins that carry out other essential cellular functions, thus increasing the potential for off target side effects.

“What was exciting in our structure of PARP-1 is that there are specialized sites on the protein that can be inhibited; you can effectively kill catalytic activity without having to touch the catalytic active site,” said Dr. Pascal.

Using X-ray crystallography, researchers studied the interaction amongst the component domains of PARP-1 and their combined role in binding to DNA damage.  The PARP-1/DNA structure revealed a network of interdomain contacts formed upon DNA binding. These domains have to come together and assemble, the researchers found, to have catalytic activity.

“Our work indicates that we should be looking for inhibitors that prevent these domains from coming together,” Dr. Pascal said. “Rather than screen for inhibitors with catalytic activity as a readout, we can screen for inhibitors that disrupt the communication between the PARP-1 domains, which would in turn shut down catalytic activity.”

Closer attention to these specialized domains could inspire the design of a new class of PARP inhibitors.

“Dr. Pascal’s structural and biochemical characterization reveals how recognition of DNA damage and communication between domains control the activity of PARP‑1,” said Barbara Gerratana, Ph.D., who oversees enzyme catalysis grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partially supported the study. “This work is a major breakthrough in understanding an enzyme essential for regulation of cell proliferation and a promising target for cancer therapeutics.”

Other researchers include Marie-France Langelier, Ph.D., Jamie L. Planck, and Swati Roy of the Department of Biochemistry and Molecular Biology at Jefferson.

This work was supported by funds from the National Institutes of Health (5R01GM087282-02), the American Cancer Society, and the Kimmel Cancer Center X-ray Crystallography and Molecular Characterization Facility at Thomas Jefferson University.



Dr. Jeannie Hoffman-Censits leads Walk for Bladder Cancer

On Saturday, May 5, 2012 Jeannie Hoffman-Censits, M.D. led Team Jefferson from the Kimmel Cancer Center‘s Bluemle Life Sciences Building to Independence Hall. Dr. Hoffman-Censits teamed up with “the first national advocacy organization devoted to bladder cancer,” the Bladder Cancer Advocacy Network, to help raise public awareness of bladder cancer and much needed funding.

Team Jefferson will be walking again on May 4, 2013. For more information, please contact Jessica Soens at Jessica.Soens@JeffersonHospital.org or call 215-955-2054.



Dr. Ronald Myers selected to chair Expert Working Group discussion

Ronald E. Myers, Ph.D.

Ronald Myers, Ph.D., Professor of Medical Oncology and Director of the Division of Population Science at Thomas Jefferson University, has been selected to chair an Expert Working Group discussion at the World Endoscopy Organization meeting on May 18, 2012. The discussion entitled “Improving Population Engagement in Screening” is being held ahead of the DDW Conference in San Diego, CA. and will be the Expert Working Group’s first meeting. The focus of this discussion is Engaging Populations in International CRC Screening Programs.

For more information on this event please contact Dr. Myers at Ronald.Myers@Jefferson.edu or 215-503-4085.



Scott Waldman Awarded CURE Grant to Move Colon Cancer Test Closer to Commercialization

Scott Waldman, M.D., Ph.D.

Scott Waldman, M.D., Ph.D., Chair of the Department of Pharmacology and Experimental Therapeutics at Thomas Jefferson University, has been awarded a Commonwealth Universal Research Enhancement (CURE) grant for almost $750,000 to help advance a molecular diagnostic test for colon cancer into commercialization.

Such a test would better detect recurrence in a group of colon cancer patients whose metastases are hidden, and help reduce racial disparities, particularly in the African-American community, who are at higher risk of dying from metastatic disease.

The nonformula grant was awarded competitively from the Pennsylvania Department of Health. One of this year’s priorities for the Department’s Health Research Advisory Committee is Cancer Diagnostics or Therapeutics with Commercialization Potential.

About 25 percent of colon cancer patients who are deemed node-negative, or pN0, (meaning the cancer has not spread to the lymph nodes) after treatment end up recurring with metastatic disease.  Known as occult tumors, these hidden metastases often escape detection, be it imaging modalities or histopathology.

Today, no such test exists to distinguish these colon cancer patients, and as a result, they are often treated the same.

To better stratify this group, Dr. Waldman and colleagues have developed a diagnostic test that uses the hormone receptor guanylyl cyclase C (GCC) as a biomarker.

Previous research shows that a quantitative, molecular analysis of lymph nodes in patients deemed colorectal cancer-free was found to be an effective predictor of recurrence. Expression of GCC in the nodes, they found, is associated with an increased risk.

“This approach can improve prognostic risk stratification and chemotherapeutic allocation for these colon cancer patients,” said Dr. Waldman, a member of Jefferson’s Kimmel Cancer Center. “With this CURE grant, we can now move a much-needed technology closer to commercialization, meaning closer to patients.”

The test will ultimately determine who can benefit from adjuvant chemotherapy, which is designed to eradicate whatever occult disease is left after surgery and other treatments.

This test would benefit the African-American community, in particular. Beyond the general population risk, there is an established stage-specific difference in outcomes in pN0 African Americans, who are 40 percent more likely to die from the metastatic colon cancer than whites.

Stratifying these patients could ultimately reduce related racial disparities in mortality and survival.

The primary purpose of this nonformula grant is to support research activities that commercialize and bring to market new cancer diagnostics and therapeutics for which proof of concept has previously been demonstrated and has the capability to solve or diminish a specific problem related to the diagnosis or treatment of one or more malignant diseases.



You Can Help Save PA Research Funding

For more than a decade, Pennsylvania’s Commonwealth Universal Research Enhancement Program (CURE) has supported a broad range of biomedical research at 39 institutions across Pennsylvania. These funds have led to research advances in cancer, cardiovascular disease, diabetes, infectious diseases, and other health areas and improvements in public health.

In his budget for fiscal year 2013, Governor Corbett proposes defunding the CURE program created by Act 77 in 2001, diverting almost $60 million in research funds from the tobacco settlement into the general budget for other purposes.

If the defunding takes place, Jefferson stands to lose $2 to $4 million per year in research funding.

Left intact with sustained funding, the CURE program will advance promising medical discoveries, support the hiring and retention of skilled workers, leverage federal and private research funding, and catalyze the formation of biotechnology companies.

Please voice your support of the CURE program by taking a moment to send a note (see suggested letter HERE) to your PA State representative. You can find your representative on this website.

Jefferson’s Kimmel Cancer Center is a member of the Pennsylvania Cancer Alliance.



Dawn Scardino named 2012 LLS Woman of the Year

Dawn Scardino named LLS Woman of the Year

Dawn Scardino, Coordinator of Academic Services in the Department of Medical Oncology, was named the 2012 Leukemia & Lymphoma Society’s Woman of the Year for the eastern Pennsylvania Chapter.

Dawn took the top recognition for raising almost $27,000 in a 10-week fundraising “race” that began on Jan. 30 and ended on April 12.  Four women and nine men took part in the race.

Participants had 10 weeks (Dawn did it in eight!) to organize and run their campaigns, with the goal of raising the most money in their chapters. The man and woman who raises the most are named the winners.

The winners–the top male prize went to Anthony Falco, who raised over $200,000–were announced at the Grand Finale Celebration at the Union League of Philadelphia on April 12.

In total, the whole group raised almost $443,000.

All proceeds from the effort go to the LLS, whose mission is to cure leukemia, lymphoma, Hodgkin’s disease and myeloma, and to improve the quality of life for patients with these diseases.

The funds Dawn raised are in honor of LLS’s Boy of the Year, Andrew Clark, a 13-year-old leukemia survivor who began his battle with acute lymphoblastic leukemia, or ALL, at the age of 3.

Since 1949, the LLS has funded over $680 million in medical research aimed at curing different cancers. LLS supports therapies that not only help blood cancer patients but are now used to treat patients with rare forms of stomach and skin cancers and are being tested in clinical trials for patients with a range of cancers including lung, brain, breast, pancreatic and prostate.

Dawn started at Jefferson in 1991.  Since her arrival in Medical Oncology in 2008 she has helped with the recruitment of 27 new faculty members to the department. This was Dawn’s first year participating in the LLS campaign race.



Kimmel Cancer Center Founding Directors Portrait Unveiled


Dr. Richard G. Pestell, Martha Mayer Erlebacher, Dr. Carlo M. Croce, Dr. Richard L. Davidson

A portrait of Dr. Carlo Croce, the founding Director of the Jefferson Kimmel Cancer Center, painted by Philadelphia artist Martha Erlebacher, was unveiled on Tuesday, April 10, 2012, at 4:00 PM in the Bluemle Life Sciences Building.

Martha Mayer Erlebacher has been recognized as one of the leading representational figurative and still-life artists in America who has shown her work nationally and internationally. A number of books and periodicals feature her work, much of which “examines the deep metaphorical and social themes of contemporary culture through her painterly and aesthetic images.”

Dr. Croce is world-renowned for his contributions involving the genes and genetic mechanisms implicated in the pathogenesis of human cancer. He is a member of the National Academy of Sciences and Institute of Medicine in the United States and the Accademia Nazionale delle Scienze detta deiXL in Italy. He has earned a plethora of awards in recognition of his hard work and dedication including two Outstanding Investigator awards from the National Cancer Institute and most recently, an Elected Membership to The American Academy of Arts and Sciences.

Dr. Joesph S. Gonnella and Dr. Carlo M. Croce

Dr. Croce is a principal investigator on eleven federal research grants and has more than 950 peer-reviewed, published research papers. A native of Milan, Italy, Dr. Croce earned his medical degree, summa cum laude, in 1969 from the School of Medicine, University of Rome. He began his career in the United States the following year as an associate scientist at the Wistar Institute of Biology and Anatomy in Philadelphia. In 1980, he was named Wistar Professor of Genetics at the University of Pennsylvania and Institute Professor and Associate Director of the Wistar Institute, titles he held until 1988. From 1988-91, he was Director of the Fels Institute for Cancer Research and Molecular Biology at Temple University School of Medicine in Philadelphia.

In 1991 Dr. Croce was named Director of the Kimmel Cancer Institute at Thomas Jefferson University.  While here, Dr. Croce discovered the role of microRNAs in cancer pathogenesis and progression, implicating a new class of genes in cancer causation.  After thirteen years as Director of the Kimmel Cancer Center, Dr. Croce moved to Ohio State University in 2004.  Under his direction at OSU, faculty within the Human Cancer Genetics Program conduct both clinical and basic research.  Basic research projects focus on how genes are activated and inactivated, how cell-growth signals are transmitted and regulated within cells, and how cells interact with the immune system. Clinical research focuses on discovering genes linked to cancer and mutations that predispose people to cancer.



Leading the Way to a Cure

It is estimated that more than 70,000 new cases of bladder cancer were diagnosed in 2011, making it the fifth most commonly diagnosed cancer in the U.S.

Please join Team Jefferson and Dr. Jean Hoffman-Censits of the Department of Medical Oncology, Solid Tumor Division and the Kimmel Cancer Center at Jefferson in raising awareness of the disease.

This year’s walk will begin at the Kimmel Cancer Center’s Bluemle Life Sciences Building. Walk with us to Independence Hall, where we will have a tent and table with refreshments and information about bladder cancer and treatment options at Jefferson.

Can’t make it to the walk? Please consider donating to the team. All proceeds will benefit the Bladder Cancer Advocacy Network, host of the annual Bladder Think Tank – the only national scientific meeting focusing solely on bladder cancer. For more information, visit www.bcan.org.

Date and Time: May 5, 2012 at 10 a.m

Location:

Bluemle Life Sciences Building
233 South 10th Street
Philadelphia, PA 19107

Registration Info:

Registration is free and fundraising is optional. Preregister for the event online or contact Teresa Bryant at 215-503-5455 or teresa.bryant@jefferson.edu.



Edith Mitchell, M.D., FACP, Named 2012 Recipient of ASCO Humanitarian Award

Edith Mitchell, M.D., to receive 2012 Humanitarian Award at ASCO annual meeting

Edith  Mitchell, M.D., FACP, a medical oncologist at Thomas Jefferson University Hospital and Jefferson’s Kimmel Cancer Center (KCC) and Clinical Professor of Medicine and Medical Oncology in the Department of Medical Oncology at Jefferson Medical College of Thomas Jefferson University, has been named the 2012 recipient of the American Society of Clinical Oncology (ASCO) Humanitarian Award for her personification of the society’s mission and values, and for going above and beyond the call of duty in providing outstanding patient care.

For her efforts, Dr. Mitchell will be presented with the award during the opening session of the ASCO Annual Meeting on Saturday, June 2.

The ASCO Humanitarian Award recognizes an oncologist who provides outstanding patient care through innovative means or exceptional service or leadership in the United States or abroad. It is presented to an ASCO member who distinguishes himself/herself through voluntary and non-compensated humanitarian endeavors.

“Receiving this award is a great honor, and I thank the Society for the acknowledgement,” said Dr. Mitchell. “A big part of my work over the course of my career has focused on helping those in need of medical care—to reach those who have no access to it, who have no opportunities for health, and no means to seek out conventional medical advice. It is important to help these individuals realize that simple changes in lifestyle can have a dramatic impact on cancer care and one’s health. I look forward to continuing on this path.”

Dr. Mitchell has spent her medical career helping individuals in medically underserved areas and demonstrating the importance of community service and outreach. She has participated in flood relief, supportive patient advocacy, and organized vaccination clinics.

Dr. Mitchell also serves as a program leader of Gastrointestinal Oncology at JMC, Associate Director for Diversity Programs for the KCC, and Director of the KCC’s newly established Center to Eliminate Cancer Disparities.

In addition to her professional roles, she has spent many years in service with the U.S. Air Force and the Air National Guard. Dr. Mitchell entered active duty after completion of her internship and residency in Internal Medicine at Meharry Medical College and a fellowship in Medical Oncology at Georgetown University. She is now a retired brigadier General from the United States Air Force.

Dr. Mitchell received a Bachelor of Science in Biochemistry “With Distinction” from Tennessee State University and her medical degree from the Medical College of Virginia in Richmond.

Dr. Mitchell’s research in pancreatic cancer and other gastrointestinal malignancies involves new drug evaluation and chemotherapy, development of new therapeutic regimens, chemoradiation strategies for combined modality therapy, patient selection criteria and supportive care for patients with gastrointestinal cancer.

As a distinguished researcher, she has received numerous Cancer Research and Principal Investigator Awards, and serves on the National Cancer Institute Review Panel and the Cancer Investigations Review Committee.  She has also authored and co-authored more than 100 articles, book chapters, and abstracts on cancer treatment, prevention, and cancer control. And in 2011, she was named “Practitioner of the Year” Award by the Philadelphia County Medical Society.

She also travels nationally and internationally teaching and lecturing on the treatment of gastrointestinal malignancies.

Dr. Mitchell is one of 12 honorees to receive an ASCO Special Award.

“All of the oncology professionals and leaders who will be receiving this year’s Special Awards have made a great impact on cancer prevention, care and treatment around the globe,” said George Sledge, M.D., ASCO Immediate Past President and Chair of the Special Awards Selection Committee. “We are honored to commend their contributions and accomplishments in the field of oncology with ASCO’s most prestigious awards.”

For more on Dr. Mitchell’s award, please see:

http://www.asco.org/ASCOv2/Press+Center/Latest+News+Releases/Meetings+News/Oncology+Professionals+and+Leaders+Honored+for+Contributions+in+the+Progress+Against+Cancer

http://www.cancer.net/patient/Publications+and+Resources/Find+an+Oncologist/ASCO+Humanitarian+Award



Ovarian, Glioblastoma & Non-Small Cell Lung Cancer: Jefferson Researchers Present at AACR

Several researchers from Jefferson’s Kimmel Cancer Center presented abstracts at the American Association for Cancer Research Annual Meeting 2012 in Chicago. Some of those findings include:

HuR and Ovarian Cancer

Silencing HuR may be a promising therapeutic approach for the treatment of ovarian cancer, according to an abstract presented at AACR by researchers from Thomas Jefferson University, Lankenau Institute for Medical Research, the Geisinger Clinic and the Massachusetts Institute of Technology.

HuR is a RNA-binding protein that post-transcriptionally regulates genes involved in the normal cellular response to cancer-associated stressors, like DNA damage, nutrient depletion and therapeutic agents.  When triggered by stress, HuR translocates from the nucleus to the cytoplasm where it potently influences translation of key tumor promoting mRNAs by mRNA stabilization and direct facilitation of translation.

Previously, it has been shown that HuR expression is a prognostic marker in ovarian cancers. Thus, researchers tested the effects of manipulating HuR expression levels on ovarian tumor growth characteristics and tested the hypothesis that silencing HuR through delivery of an HuR siRNA would be effective in suppressing the growth of ovarian tumors.

Following treatment of ovarian cancer cells in culture with an adenovirus containing the HuR coding sequence, HuR expression was increased by about 40% above control cells.

In the patient cohort, researchers also detected HuR activation (i.e., cytoplasmic HuR positivity) in twenty-four of thirty four patients (71 percent), providing evidence that the majority of patients have activated HuR.

“These data provide evidence that silencing HuR, even as a monotherapeutic strategy, may be a promising therapeutic approach for the treatment of ovarian cancer,” wrote the authors.

Authors of the paper include Janet A. Sawicki and Yu-Hung Huang, of Lankenau Institute for Medical Research, Charles J. Yeo, Agnieszka K. Witkiewicz, Jonathan R. Brody, of Thomas Jefferson University, Radhika P. Gogoi, of Geisinger Clinic, Danville, Pa., and Kevin Love and Daniel G. Anderson, of Massachusetts Institute of Technology, Cambridge, Mass.

This work was supported by the Marsha Rivkin Center for Ovarian Cancer Research.

Radiotherapy and Glioblastoma

Radiotherapy’s effect on glioblastoma (GBM) is enhanced in the presence of a heat shock protein and a P13K inhibitor, researchers from the Department of Radiation Oncology reported at AACR.

Glioblastoma tumors frequently contain mutations in the tumor suppressor gene, PTEN, leading to loss of PTEN activity, which causes overactivation of the PI3K pathway, inducing inhibition of apoptosis and radioresistance.

Heat-shock protein 90 (HSP90) is a molecular chaperone that is over-expressed in GBM and that has among its client proteins, PI3K and Akt.

It was hypothesized that dual inhibition of HSP90 and PI3K signaling would additively or synergistically radiosensitize GBM through inhibition of radiation-induced PI3K/Akt signaling, leading to enhanced apoptosis.

Confirming their theory, the researchers found that the response of glioblastoma to radiotherapy was enhanced in the presence of BKM120 and HSP990. Enhanced apoptosis also contributed to the mechanism of cell death.

Authors of the study include Phyllis Rachelle Wachsberger, Yi Liu, Barbara Andersen, and Adam P. Dicker, of the Department of Radiation Oncology at Thomas Jefferson University Hospital and Richard Y. Lawrence, of Jefferson and the Sheba Medical Center, Tel Hashomer, Israel.

This work was supported by a grant from Novartis Pharmaceuticals.

Non-Small Lung Cancer and DACH1

Researchers from the Kimmel Cancer Center at Jefferson have identified a protein relationship that may be an ideal treatment target for non-small cell lung cancer (NSCLC).  They presented their findings at AACR.

DACH1, a cell fate determination factor protein, appears to be a binding partner to p53, a known tumor suppressor, which inhibits NSCLC cellular proliferation.

As cancer develops and becomes more invasive, the expression of DACH1 decreases. Clinical studies have demonstrated a reduced expression of the DACH1 in breast, prostate and endometrial cancer.

In a previous study of more than 2,000 breast cancer patients, Jefferson researchers found that a lack of DACH1 expression was associated with a poor prognosis in breast cancer patients. Patients who did express DACH1 lived an average of 40 months longer.

Genetic studies have identified several oncogenes activated in lung cancer, including K-Ras and EGFR. Given the importance of the EGFR in human lung cancer, researchers examined the role of DACH1 in lung cancer cellular growth, migration and DNA damage response.

For this study, endogenous DACH1 was reduced in human NSCLC, with expression levels of DACH1 correlating inversely with clinical stage and pathological grade.

Re-expression of DACH1 also  reduced lung cancer cell colony formation and cellular migration. Cell cycle analyses demonstrated that G2/M block by ectopic expression of DACH1 occurs synergistically with p53.

Fluorescent microscopy demonstrated co-localization of DACH1 with p53, and immunoprecipitation and western blot assay showed DACH1 association with p53.

“DACH1 enhanced the cytotoxcity of cisplatin and doxorubicin, two commonly used drugs for NSCLC,” the authors write in the abstract. “Together, our studies demonstrate that p53 is a DACH1 binding partner that inhibits NSCLC cellular proliferation.”

Authors of the study include Ke Chen, Kongming Wu, Wei Zhang, Jie Zhou, Timothy Stanek, Zhiping Li, Chenguang Wang, L. Andrew Shirley, Hallgeir Rui, Steven McMahon, Richard G. Pestell, of  Thomas Jefferson University, Kimmel Cancer Center and Huazhong University of Science and Technology, Wuhan, China.