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UPCI Awarded Nearly $10 Million in Prestigious NCI Grants to Foster Cancer Research

PITTSBURGH, April 24, 2014 – The University of Pittsburgh Cancer Institute (UPCI) has been awarded two highly sought-after grants from the National Cancer Institute (NCI), totaling nearly $10 million, that will aid in bringing the latest research developments from bench to bedside and accelerate research into such things as rare tumors. UPCI is one of only 12 centers in the country to receive the NCI Experimental Therapeutics-Clinical Trials Network with Phase I Emphasis grant and the only center in Pennsylvania to receive a Lead Academic Participating Site (LAPS) grant under the NCI’s new clinical trials network.

That’s good news to patients like Patrick Jackson, who was diagnosed with a rare cancer known as grade I myxopapillary-ependymomas a few years ago. Jackson was referred to UPMC, where doctors treat just a couple of cases like his each year. He said any developments that can speed research and help cancer patients is a good thing.

“I am so fortunate that my ependymoma is low grade and has responded so well to treatment,” Jackson said. “I would just want people to know that there is hope, and there is nothing more comforting than having doctors familiar with your disease.”

The awards are further evidence of UPCI’s place as one of the premier academic cancer research centers in the country. UPCI is the only NCI-designated comprehensive cancer center in western Pennsylvania and through the network of its clinical partner, UPMC CancerCenter, enables several thousand patients to participate in clinical trials each year.

“Participating in a clinical trial is the optimal form of therapy for patients who are willing and able and allows us to learn something for the future along the way. We are grateful for the support of our patients and providers who have been an integral part of our success and helped us attain these two very important awards,” said Nancy E. Davidson, M.D., director of UPCI and the UPMC CancerCenter.

The NCI Experimental Therapeutics-Clinical Trials Network with Phase I Emphasis grant is led by UPCI Deputy Director Edward Chu, M.D. The $4.25 million, five-year grant funds complex research into new drug therapies.

“Our focus is on developing completely novel agents and combination regimens. We also are trying to understand how some of these new targeted therapies work and how we can apply science to individually tailor these new treatments to specific cancers,” Dr. Chu said.

UPCI is uniquely qualified to lead efforts in drug development because of the team approach that goes into the research, he noted, with expertise in pharmacokinetics, pharmacodynamics and basic science.

“We have a large patient base that allows us to do these novel first-in-man studies. The large majority of the patients who are referred to us have failed standard-of-care therapies, and they are looking for new treatments. There is only a small handful of cancer centers across the country that can offer the types of phase I clinical studies available to our patients here in Pittsburgh and the western Pennsylvania region,” Dr. Chu said.

The LAPS grant is part of the new National Clinical Trials Network (NCTN), designed to speed up the time it takes research to get from the lab to patients through technological advances and enhanced cooperation. The nearly $5 million award is led by Adam Brufsky, M.D., Ph.D., UPCI’s associate director for clinical investigation. The grant will fund the costs of maintaining a clinical trials infrastructure that permits patients to enroll in national trials led by the NCTN at more than a dozen sites across the UPMC CancerCenter network.

“This grant is tremendous validation from the NCI about the important and cutting-edge work that we are doing here at UPCI and our ability to shape what’s happening in cancer research across the country. We’re excited to play a vital role in this new system and expand access to trials all over western Pennsylvania,” Dr. Brufsky said.

As part of the award, Dr. Brufsky will lead a group at UPCI that includes Dwight E. Heron, M.D., Mark Socinski, M.D.; John Kirkwood, M.D., and Robert P. Edwards, M.D.

The NCTN replaces the cooperative networks that existed previously and were based on a model developed more than half a century ago. NCI officials hope to speed research through improvements in data management infrastructure, the development of a standardized process for prioritization of new studies, consolidation of its component research groups to improve efficiency, and the implementation of a unified system of research subject protection at over 3,000 clinical trials sites.

One important outcome of this new network will be the ability to facilitate the conduct of trials in rare tumors where patient accrual has always been very difficult. The availability of a national network of clinical trials sites to locate and enroll patients with unusual cancers should enhance the feasibility of conducting such studies. Also, as more cancers are molecularly defined and classified into smaller subsets, the new network structure will support the molecular screening studies needed to define and locate the smaller groups of patients who might be eligible for such studies.

“It has always been our mission at UPMC CancerCenter to provide the best care possible to patients in their own communities, and this grant enhances our ability to do that,” Dr. Davidson said.

Malfunction in Molecular ‘Proofreader’ Prevents Repair of UV-Induced DNA Damage

PITTSBURGH, April 21, 2014 – Malfunctions in the molecular “proofreading” machinery, which repairs structural errors in DNA caused by ultraviolet (UV) light damage, help explain why people who have the disease xeroderma pigmentosum (XP) are at an extremely high risk for developing skin cancer, according to researchers at the University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute (UPCI). Their findings will be published this week in the early online version of the Proceedings of the National Academy of Sciences.

Previous research has shown that a DNA-repair protein called human UV-damaged DNA-binding protein, or UV-DDB, signals for a repair when two UV-DDB molecules bind to the site of the problem, said senior investigator Bennett Van Houten, Ph.D., the Richard M. Cyert Professor of Molecular Oncology, Pitt School of Medicine, and co-leader of UPCI’s Molecular and Cell Biology Program.

“Our new study shows UV-DDB makes stops along the DNA strand and transiently attaches to it, causing a proofreading change in the protein’s conformation, or shape. If the DNA is damaged the protein stays, if the DNA is not damaged the protein leaves,” Dr. Van Houten said. “When it comes to a spot that has been damaged by UV radiation, two molecules of UV-DDB converge and stay tightly bound to the site, essentially flagging it for the attention of repair machinery.”

The researchers followed the trail of single molecules of UV-DDB by tagging them with light-emitting quantum dots, enabling them to watch the molecules jump from place to place in real time on both normal and UV-exposed DNA strands.

They also tracked a mutant UV-DDB protein associated with XP, an inherited, incurable disease of light sensitivity that affects about 1 in 250,000 people. They found that the mutant UV-DDB molecules are still capable of binding to DNA, but continued to slide along the DNA rather than staying put to signal where the fix was needed.

“Without this important damage control, UV-induced errors could accumulate to cause cell alterations that foster cancer development,” Dr. Van Houten said. “Like a bus with no brakes, the XP-associated UV-DDB complex stays on the road and sees possible passengers, but keeps going past the stop.”

Co-investigators include Harshad Ghodke, Ph.D., Ching L. Hsieh, Selamawit Woldemeskel, Simon C. Watkins, Ph.D., and Vesna Rapic-Otrin, Ph.D., all of the University of Pittsburgh School of Medicine; and Hong Wang, Ph.D., of North Carolina State University.

The project was funded by the University of Pittsburgh Cancer Institute Cancer Center Support grant CA 047904 and National Institutes of Health grant ES019566.

Common Breast Cancer Subtype May Benefit From Personalized Treatment Approach, UPCI Finds

SAN DIEGO, April 4, 2014 – The second-most common type of breast cancer is a very different disease than the most common and appears to be a good candidate for a personalized approach to treatment, according to a multidisciplinary team led by scientists at the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter.

Invasive lobular carcinoma, characterized by a unique growth pattern in breast tissue that fails to form a lump, has distinct genetic markers which indicate drug therapies may provide benefits beyond those typically prescribed for the more common invasive ductal carcinoma. The results recently were published in Cancer Research and will be expanded upon on Tuesday at the American Association for Cancer Research (AACR) Annual Meeting 2014.

Patients with invasive lobular carcinoma typically are treated through surgical removal of the cancer, followed by chemotherapy or hormone therapy or both, usually with the estrogen-mimicking drug tamoxifen or estrogen-lowering aromatase inhibitors, the same as patients with invasive ductal carcinoma.

“However, recent analyses suggest that a subset of patients with lobular carcinoma receive less benefit from adjuvant tamoxifen than patients with ductal carcinoma,” said lead author Matthew Sikora, Ph.D., postdoctoral associate at UPCI, and recipient of this year’s AACR-Susan G. Komen Scholar-in-Training Award for this research. “Our study, the largest of its kind, indicates an issue with the estrogen receptors inside lobular carcinoma cells and points to potential targets for drug therapy in future clinical trials, which we are developing.”

Early studies in developing these potential targets are the topic of Dr. Sikora’s AACR presentation, with a focus on a unique signaling pathway regulated by estrogen specifically in lobular carcinoma cells.

Additional researchers on this study include Steffi Oesterreich, Ph.D., and Amir Bahreini, B.S., both of UPCI.

This research was supported by the Breast Cancer Research Foundation, Department of Defense Breast Cancer Research Program and Pennsylvania Department of Health.

Combining Cell Replication Blocker with Common Cancer Drug Kills Resistant Tumor Cells, UPCI Researchers Find

SAN DIEGO, April 4, 2014 – Researchers from the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter, have found that an agent that inhibits mitochondrial division can overcome tumor cell resistance to a commonly used cancer drug, and that the combination of the two induces rapid and synergistic cell death. Separately, neither had an effect. These findings will be presented Monday at the annual meeting of the American Association for Cancer Research Annual Meeting 2014.

“In our earlier work, we found that blocking production of a protein called Drp1 stopped mitochondria, known as the powerhouses of the cell, from undergoing fission, which is necessary for the cellular division process called mitosis,” said Bennett Van Houten, Ph.D., the Richard M. Cyert Professor of Molecular Oncology, Pitt School of Medicine, and leader of UPCI’s Molecular and Cell Biology Program. “The loss of this critical mitochondrial protein caused the cells to arrest in mitosis and to develop chromosomal errors, and eventually led the tumor cell into the cell death pathway known as apoptosis.”

The researchers blocked Drp1 in breast cancer cell lines with an agent called mitochondrial division inhibitor-1 (mdivi-1) and found that when mdivi-1 and the cancer drug cisplatin were given together, they caused DNA damage, DNA replication stress, and greater than expected apoptosis rates. The synergistic drug combination acted through two independent biochemical pathways that caused the mitochondrial membrane to swell, increasing its permeability and allowing the leak of chemical signals that trigger apoptosis.

“Cisplatin is one of the most widely used cancer drugs today, but some tumors are inherently resistant to it, and many others become resistant, leading to treatment failure,” Dr. Van Houten said. “In our studies, this combination overcame cisplatin resistance and caused cancer cell death, which is very encouraging.”

The team is testing the regimen’s effectiveness in a mouse model of ovarian cancer, a disease that often recurs and no longer responds to cisplatin treatment.

Screening Reveals Additional Link Between Endometriosis and Ovarian Cancer

SAN DIEGO, April 4, 2014 – Some women with endometriosis, a chronic inflammatory disease, are predisposed to ovarian cancer, and a genetic screening might someday help reveal which women are most at risk, according to a University of Pittsburgh Cancer Institute (UPCI) study, in partnership with Magee-Womens Research Institute (MWRI).

Monday at the American Association for Cancer Research (AACR) Annual Meeting 2014, UPCI and MWRI researchers will present the preliminary results of the first comprehensive immune gene profile exploring endometriosis and cancer.

“A small subset of women with endometriosis go on to develop ovarian cancer, but doctors have no clinical way to predict which women,” said senior author Anda Vlad, M.D., Ph.D., assistant professor of obstetrics, gynecology and reproductive sciences at MWRI. “If further studies show that the genetic pathway we uncovered is indicative of future cancer development, then doctors will know to more closely monitor certain women and perhaps take active preventative measures, such as immune therapy.”

Endometriosis is a painful, often invasive and recurrent condition that happens when the tissue that lines the uterus grows outside of the uterus, causing inflammation. It affects approximately one in 10 women.

By screening tissue samples from women with benign endometriosis, endometriosis with precancerous lesions and endometriosis-associated ovarian cancer, Dr. Vlad and her colleagues identified the complement pathway, which refers to a series of protein interactions that trigger an amplified immune response, as the most prominent immune pathway that is activated in both endometriosis and endometriosis-associated ovarian cancer.

“If, as our study indicates, a problem with the immune system facilitates cancer growth through chronic activation of the complement pathway, then perhaps we can find ways to change that and more effectively prime immune cells to fight early cancer, while controlling the complement pathway,” said lead author Swati Maruti Suryawanshi, Ph.D., a post-doctoral research fellow at MWRI.

Instrumental to this multidisciplinary study were Robert P. Edwards, M.D., and Esther Elishaev, M.D., both of Magee-Womens Hospital of UPMC, and Xin Huang, Ph.D., MWRI. Additional contributors are Raluca Budiu, Ph.D., SungHwan Kim, Ph.D., and George Tseng, Ph.D., all of Pitt; and Marcia Klein-Patel, M.D., Ted Lee, M.D., Suketu Mansuria, M.D., all of UPMC.

This research was funded by UPMC grant 02.93530.

Genetic Testing Beneficial in Melanoma Treatment, UPCI Study Shows

SAN DIEGO, April 4, 2014 – Genetic screening of cancer can help doctors customize  treatments so that patients with melanoma have the best chance of beating it, according to the results of a clinical trial by researchers at the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter.

The trial, funded by the National Institutes of Health (NIH), will be presented Monday at the American Association for Cancer Research (AACR) Annual Meeting 2014. It showed that the cancer immune therapy drug ipilimumab appears most likely to prevent recurrence in patients whose cancer shows high expression of immune-related genes.

“We’ve reached a point in the treatment of melanoma — and cancer in general — where we’re making major improvements in the outcomes of patients through personalized medicine,” said lead investigator Ahmad Tarhini, M.D., Ph.D., associate professor of medicine and translational science in Pitt’s Department of Medicine and Clinical and Translational Science Institute. “Anti-cancer therapy can be associated with significant side effects and economic costs. Therefore, we have a major interest in the development of tests that may allow us to predict which treatment regimen is most likely to help certain patients, while sparing others the unwanted side effects and cost of medications that are unlikely to work.”

Before and after ipilimumab treatment, Dr. Tarhini and his colleagues obtained tumor biopsies used to run genetic tests on the tumors of 32 patients with advanced, stage 3 melanoma who were treated by UPMC. All patients were given standard-of-care surgery, which included complete surgical removal of an advanced tumor.

Patients with tumors that had higher levels of expression of a group of immune-related genes, either before or soon after treatment with ipilimumab, had 63 percent lower risk of cancer recurrence after surgery.

“By validating these findings in a large national trial that also will allow us to investigate other significant biomarker data, we’ll seek to develop ‘biomarker signatures’ that doctors can use to customize melanoma treatment plans. The ultimate goals of therapy are to best treat the cancer in an individualized approach, while avoiding the unnecessary exposure of patients to severe side effects,” said Dr. Tarhini.

Additional researchers on this study are Yan Lin, Ph.D., Hui-Min Lin, M.S., Cindy Sander, B.S., William A. La Framboise, Ph.D., and John M. Kirkwood, M.D., all of UPCI.

This research was supported by NIH award P50CA121973 and Bristol-Myers Squibb.

Plant-Derived Anti-Cancer Compounds Explained at National Conference

SAN DIEGO, April 4, 2014 – Compounds derived from plant-based sources — including garlic, broccoli and medicine plants — confer protective effects against breast cancer, explain researchers at the University of Pittsburgh Cancer Institute (UPCI), partner with the UPMC CancerCenter.

In multiple presentations Sunday at the American Association for Cancer Research (AACR) Annual Meeting 2014, UPCI scientists will update the cancer research community on their National Cancer Institute (NCI)-funded findings, including new discoveries about the mechanisms by which the plant-derived compounds work.

“In recent years, we’ve made some very encouraging discoveries indicating that certain plants contain cancer-fighting compounds,” said Shivendra Singh, Ph.D., UPMC Chair in Cancer Prevention Research and professor in Pitt’s Department of Pharmacology & Chemical Biology. “By understanding the molecular mechanisms by which these plant-derived compounds work against breast cancer, we hope to find efficient ways to use them to prevent and fight cancer in patients.”

At the AACR poster session “Mechanisms of Chemoprevention,” Dr. Singh will oversee four presentations by Pitt pharmacology & chemical biology researchers on plant-derived compound discoveries in his laboratory.

  • Dr. Singh will discuss how withaferin A, derived from an Indian medicine plant, binds to tubulin, a well-known target for drug treatment in breast and other cancers. This compound binds tubulin in the cancer at a site distinct from those affected by other clinically used tubulin targeting agents. Notably, this effect of withaferin A is selective for cancerous breast cells.
  • Eun-Ryeong Hahm, Ph.D., will discuss how diallyl trisulfide, an oil-soluble molecule created by chewing of allium vegetables, such as garlic, decreases levels of the estrogen receptor-alpha protein in breast cancer cells and inhibits growth of breast cancer stem cells by decreasing levels of two other proteins.
  • Su-Hyeong Kim, Ph.D., will discuss how benzyl isothiocyanate, a molecule found in edible cruciferous vegetables, such as garden cress, works in breast cancer cells to decrease levels of Bmi-1, a protein that controls genes responsible for cell proliferation.
  • Anuradha Sehrawat, Ph.D., will discuss how breast cancer stem cell growth is inhibited when a protein called Ron sensitizes the stem cells to the benzyl isothiocyanate molecule in cruciferous vegetables. The molecule then induces breast cancer stem cell death.

This work was supported by NCI grants RO1 CA142604-04, P30 CA047904, RO1 CA113363-09 and RO1 CA129347-07.

Recurrent Head and Neck Tumors Have Gene Mutations That Could be Vulnerable to Cancer Drug

SAN DIEGO, April 4, 2014 – An examination of the genetic landscape of head and neck cancers indicates that while metastatic and primary tumor cells share similar mutations, recurrent disease is associated with gene alterations that could be exquisitely sensitive to an existing cancer drug. Researchers from the University of Pittsburgh Cancer Institute (UPCI) and Yale University School of Medicine will share their findings during a mini-symposium Sunday at the American Association for Cancer Research Annual Meeting 2014.

About 50 percent of patients diagnosed with head and neck squamous cell cancers already have disease that has spread, or metastasized, to the lymph nodes, explained Jennifer Grandis, M.D., distinguished professor and vice chair of research, Department of Otolaryngology, Pitt School of Medicine, and director of the Head and Neck Program at UPCI, partner with UPMC CancerCenter. About 20 to 30 percent of patients thought to be cured of the disease go on to develop recurrent cancer, which typically doesn’t respond to standard treatments.

“We decided to compare the genetic signatures of tumor cells from primary tumors with those from disease that had spread and cancers that were thought cured but then came back in the hopes of getting some clues about how best to guide therapy in these different settings,” Dr. Grandis said. “We found that recurrent cancers might have an Achilles’ heel we can exploit to kill them.”

The team conducted the first whole-exome genetic sequencing study on what Dr. Grandis called its “treasure trove” of frozen patient samples and found similar mutations both in primary tumors and in the lymph nodes to which their cancers had already spread. But there were different mutations in tumors that had recurred after a period of remission that were not found in their original cancers.

“The recurrent tumors carried mutations in a gene area that encodes for DDR2 cell receptors,” Dr. Grandis said. “Other studies have shown that DDR2 mutations can confer sensitivity to the cancer drug dasatinib, which could mean that drug has promise in the treatment of recurrent head and neck cancers.”

The researchers suggest that further investigation of dasatinib treatment is warranted.

Disease-Free Survival Estimates for Ovarian Cancer Improve Over Time

SAN DIEGO, April 4, 2014 – The probability of staying disease-free improves dramatically for ovarian cancer patients who already have been disease-free for a period of time, and time elapsed since remission should be taken into account when making follow-up care decisions, according to a study led by researchers at the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter.

A patient’s prognosis traditionally is determined when they are diagnosed with a disease or when they become disease-free. However, for patients who already have survived or been disease-free for a number of years, these estimates may no longer be accurate because prognosis usually improves over time. Determining a prognosis that takes into account time elapsed since remission may be a more accurate benchmark. This measure is known as conditional disease-free survival.

“Having more accurate information about the risk of recurrence will allow patients and clinicians to make better informed decisions regarding follow-up care after cancer treatment. It also may lead to patients having a better quality of life because a more accurate diagnosis can ease their fears about the cancer coming back,” said Brenda Diergaarde, Ph.D., a UPCI researcher who will present the findings Wednesday at the American Association for Cancer Research (AACR) Annual Meeting 2014.

In the study, researchers estimated disease-free survival and conditional disease-free survival for 404 ovarian cancer patients who had achieved remission and whose information was collected as part of the Hormones and Ovarian Cancer Prediction (HOPE) case-control study. The researchers found disease-free survival estimates for ovarian cancer patients improved dramatically over time, in particular among those with poorer initial prognoses. At time of remission, the probability of staying disease-free for three more years was 48 percent. This increased to 98 percent for patients who had remained disease-free for five years after remission.

Additional contributors to the study were Joel L. Weissfeld, M.D., Janet M. Catov, Ph.D., Marnie Bertolet, Ph.D., Francesmary Modugno, Ph.D., Clareann H. Bunker, Ph.D, and Michelle L. Kurta, Ph.D., all of the Department of Epidemiology, University of Pittsburgh Graduate School of Public Health; Robert P. Edwards, M.D., and Kathleen McDonough, Ph.D., both of the University of Pittsburgh Cancer Institute; Kirsten B. Moysich, Ph.D., Roswell Park Cancer Institute; and Roberta B. Ness, M.D., School of Public Health, University of Texas Health Science Center.

The research was supported by National Institutes of Health grants R01 CA095023, R01 CA126841, P30 CA047904 and R25 CA057703.

Some Breast Cancer Tumors Hijack Patient Epigenetic Machinery to Evade Drug Therapy

PITTSBURGH, March 26, 2014 – A breast cancer therapy that blocks estrogen synthesis to activate cancer-killing genes sometimes loses its effectiveness because the cancer takes over epigenetic mechanisms, including permanent DNA modifications in the patient’s tumor, once again allowing tumor growth, according to an international team headed by the University of Pittsburgh Cancer Institute (UPCI).

The finding warrants research into adding drugs that could prevent the cancer from hijacking patients’ repressive gene regulatory machinery, which might allow the original therapy to work long enough to eradicate the tumor, the researchers report in their National Institutes of Health-funded study, published in the current issue of Science Translational Medicine.

“Our discovery is particularly notable as we enter the era of personalized medicine,” said senior author Steffi Oesterreich, Ph.D., professor in Pitt’s Department of Pharmacology and Chemical Biology and at UPCI, a partner with UPMC CancerCenter, and director of education at the Women’s Cancer Research Center. “Resistance to hormonal therapy is a major clinical problem in the treatment of most breast cancers. Through testing of a tumor’s genetic and epigenetic make-up, we may be able to identify the patients most likely to develop such resistance and, in the future, create a treatment regimen tailored to giving each patient the best chance of beating their cancer.”

Epigenetic translates to “above genetic” and is an emerging field of study that looks at how environmental factors — such as infections, pollutants, stress and, in this case, long-term exposure to drugs that block estrogen synthesis — could influence a person’s DNA. Epigenetic changes do not alter the structure of the DNA, but they do change the way the DNA is modified, which subsequently determines the potential of gene regulation.

By performing a genome-wide screen in breast cancer cells, Dr. Oesterreich and her colleagues identified a gene called HOXC10 as one that the cancer seems to modify to allow continued tumor growth in patients whose cancer becomes resistant to traditional therapies.

The hormone estrogen represses genes, such as HOXC10, that induce cell death and inhibit growth. About 70 percent of breast cancer tumors are positive for a protein called ‘estrogen receptor alpha,’ which prevents HOXC10 from killing the cancer. To overcome this, doctors put these patients on anti-estrogen therapy, including aromatase inhibitors.

Unfortunately, in some cases, the tumor uses different epigenetic mechanisms, independent of estrogen, to repress the HOXC10 gene. This allows the cancer to continue growing. When the tumor uses these mechanisms, it makes deeper modifications to the expression of the patient’s DNA, permanently blocking the HOXC10 and other genes and making cancer treatment much more difficult.

“In some patients the tumors never respond to aromatase inhibitors and just keep growing. In other patients, using aromatase inhibitors to block estrogen synthesis and allow HOXC10 and other genes to destroy the cancer works in the short term,” said Dr. Oesterreich. “But, eventually, we see the tumor start to gain ground again as the cancer permanently represses genes such as HOXC10. At that point, the aromatase inhibitor is no longer effective.”

Dr. Oesterreich and her colleagues propose that future studies look at offering a combined therapy that, along with aromatase inhibitors, also introduces drugs that modify the epigenome to prevent or delay the cancer from repressing cancer-killing genes.

The researchers also note that more investigation is needed to fully understand all the mechanisms by which HOXC10 mediates cell proliferation and death, and the roles it may play in different types of tumors.

Additional researchers on this study are Thushangi N. Pathiraja, Ph.D., Shiming Jiang, Ph.D., Yuanxin Xi, Ph.D., Jason P. Garee, Ph.D., Dean P. Edwards, Ph.D., Martin J. Shea, Rachel Schiff, Ph.D., and Wei Lei, Ph.D., all of, or formerly of, Baylor College of Medicine; Shweta Nayak, M.D., of Magee-Womens Hospital of UPMC; Adrian V. Lee, Ph.D., Jian Chen, M.S., and Nancy E. Davidson, M.D., all of UPCI; Richard J. Santen, M.D., of the University of Virginia; Frank Gannon, Ph.D., and Sara Kangaspeska, Ph.D., formerly of the European Molecular Biology Laboratory and now at QIMR Berghofer Medical Research Institute in Brisbane, Australia, and at Institute for Molecular Medicine, Helsinki, Finland; Jaroslav Jelinek, M.D., Ph.D., and Jean-Pierre J. Issa, M.D., both of Temple University; Jennifer K. Richer, Ph.D., and Anthony Elias, M.D., both of the University of Colorado; and Marie McIlroy, Ph.D., and Leonie Young, Ph.D., both of the Royal College of Surgeons of Ireland.

This project was funded in part by the Alexander von Humboldt Foundation; U.S. Department of Defense grant 5W81XWH-06-1-0713; National Institutes of Health grants P30CA125123, P30CA47904, P50CA58183, P01CA030195, R01HG007538, R01CA94118 and R01CA097213; Susan G. Komen for the Cure Foundation grant PG12221410; the EIF/Lee Jeans Breast Cancer Research Program; Su2C/Breast Cancer Program; Breast Cancer Research Foundation; and Pennsylvania Department of Health.

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