UPMC Physician Resources

Archives for Cancer

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.

$2 Million NIH Grant Renews UPCI Research into Viruses, Cancer Pathways

PITTSBURGH, March 5, 2014 – The National Institutes of Health (NIH) has renewed a grant for more than $2 million for Patrick Moore, M.D., M.P.H., director of the Molecular Virology Program at the University of Pittsburgh Cancer Institute (UPCI), who will use the money to continue research into the newest human cancer virus causing most Merkel cell carcinomas.

A team led by Dr. Moore and Yuan Chang, M.D. discovered the Merkel cell polyomavirus in 2008, the seventh human cancer virus identified and the second discovered by Dr. Moore’s group under the original NIH grant that expires March 31. The new grant will fund the research through March 2019.

“Our initial grant was highly successful and led to new methods to diagnose and treat Merkel cell carcinoma,” Dr. Moore said. “We believe that these findings can help us to uncover new causes of other cancers, which may speed development and testing of new cancer therapies.”

Drs. Moore, Chang and their colleagues at Pitt identified a protein that allows the usually harmless polyomavirus to transform healthy cells into Merkel cell carcinoma, a rare but deadly skin cancer. They hope their work — which emphasizes the importance of fundamental basic science research to medical progress — can soon be translated into human clinical trials.

“Viruses are an important model for cancer research,” said Dr. Chang. “We’ve found that it may be possible to kill cancerous tumors by targeting the pathways these viruses use. That’s significant when you consider that 20 percent of all cancers are related to infectious diseases.”

The NIH grant number is R01 CA136806-06.

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

PITTSBURGH, Feb. 26, 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 University of Pittsburgh Cancer Institute (UPCI) scientists.

Invasive lobular carcinoma, which is characterized by a unique growth pattern in breast tissue that fails to form a lump, has distinct genetic markers that indicate there may be benefits from drug therapies beyond those typically prescribed for the more common invasive ductal carcinoma. The results will be published in the March 1 issue of the journal Cancer Research.

Patients with invasive lobular carcinoma are typically 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 have shown that a subset of patients with lobular carcinoma receive less benefit from adjuvant tamoxifen than patients with ductal carcinoma,” said senior author Steffi Oesterreich, Ph.D., professor at UPCI, a partner with UPMC CancerCenter, and director of education at the Women’s Cancer Research Center. “Our study, the largest of its kind, indicates an issue with the estrogen receptors inside lobular carcinoma cells and points to a potential target for drug therapy in future clinical trials, which we are developing.”

The UPCI study, funded by the Breast Cancer Research Foundation and the U.S. Department of Defense, included collaborations across multiple disciplines, ranging from biostatistics and biomedical informatics to pathology and human genetics, in order to produce results with the potential for rapid translation into clinical therapies.

“In addition to its potential clinical implications, the study highlights the need for more and better models mimicking invasive lobular cancer that can be used for laboratory studies,” said lead author Matthew Sikora, Ph.D., a postdoctoral associate at UPCI.

“Because lobular carcinomas account for only 10 to 15 percent of breast cancers, while ductal carcinomas make up nearly 80 percent, lobular carcinomas are a less attractive option for laboratory study,” said Dr. Sikora. “However, 30,000 women in the U.S. are diagnosed with lobular carcinoma every year, so there is a great need for further study of this disease.”

Additional co-authors of this study include Kristine L. Cooper, M.S., Amir Bahreini, B.S., Soumya Luthra, M.S., Uma Chandran, Ph.D., M.S.I.S., Nancy E. Davidson, M.D., and David J. Dabbs, M.D., all of Pitt; and Guoying Wang, M.S., and Alana L. Welm, Ph.D., both of the University of Utah.

This research was supported by the Breast Cancer Research Foundation, Noreen Fraser Foundation, Department of Defense Breast Cancer Research Program fellowship and Era of Hope Scholar Award, and Pennsylvania Department of Health.

Page 1 of 8:1 2 3 4 »Last »