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.




Stronger Intestinal Barrier May Prevent Cancer in the Rest of the Body, New Study Suggests

Scott Waldman, M.D., Ph.D., chair of the Department of Pharmacology and Experimental Therapeutics at Jefferson and director of the Gastrointestinal Cancer Program at Jefferson’s Kimmel Cancer Center

A leaky gut may be the root of some cancers forming in the rest of the body, a new study published online Feb. 21 in PLoS ONE by Thomas Jefferson University researchers suggests.

It appears that the hormone receptor guanylyl cyclase C (GC-C)—a previously identified tumor suppressor that exists in the intestinal tract—plays a key role in strengthening the body’s intestinal barrier, which helps separate the gut world from the rest of the body, and possibly keeps cancer at bay. Without the receptor, that barrier weakens.

A team led by Scott Waldman, M.D., Ph.D., chair of the Department of Pharmacology and Experimental Therapeutics at Jefferson and director of the Gastrointestinal Cancer Program at Jefferson’s Kimmel Cancer Center, discovered in a pre-clinical study that silencing GC-C in mice compromised the integrity of the intestinal barrier.  It allowed inflammation to occur and cancer-causing agents to seep out into the body, damaging DNA and forming cancer outside the intestine, including in the liver, lung and lymph nodes.

Conversely, stimulating GC-C in intestines in mice strengthened the intestinal barrier opposing these pathological changes.

A weakened intestinal barrier has been linked to many diseases, like inflammatory bowel disease, asthma and food allergies, but this study provides fresh evidence that GC-C plays a role in the integrity of the intestine.  Strengthening it, the team says, could potentially protect people against inflammation and cancer in the rest of the body.

“If the intestinal barrier breaks down, it becomes a portal for stuff in the outside world to leak into the inside world,” said Dr. Waldman. “When these worlds collide, it can cause many diseases, like inflammation and cancer.”

The role of GC-C outside the gut has remained largely elusive. Dr. Waldman and his team have previously shown its role as a tumor suppressor and biomarker that reveals occult metastases in lymph nodes. They’ve used to it better predict cancer risk, and have even shown a possible correlation with obesity.

Reporting in the Journal of Clinical Investigation, Dr. Waldman colleagues found that silencing GC-C affected appetite in mice, disrupting satiation and inducing obesity. Conversely, mice who expressed the hormone receptor knew when to call it quits at mealtime.

However, its role in intestinal barrier integrity, inflammation, and cancer outside the intestine is new territory in the field.

A new drug containing GC-C is now on the verge of hitting the market, but its intended prescribed purpose is to treat constipation.

This study helps lays the groundwork, Dr. Waldman said, for future pre-clinical and clinical studies investigating GC-C’s abilities beyond those treatments in humans, including prevention and treatment of inflammatory bowel disease and cancer.

“We’ve shown that when you pull away GC-C in animals, you disrupt the intestinal barrier, putting them at risk for getting inflammatory bowel disease and cancer.  And when you treat them with hormones that activate GC-C it helps strengthen the integrity of the intestinal barrier,” Dr. Waldman said.  “Now, if you want to prevent inflammation or cancer in humans, then we need to start thinking about feeding people hormones that activate GC-C to tighten up the barrier.”



Blocking Receptor in Key Hormone Fires Up Enzyme to Kill Pancreatic Cancer Cells

Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University

Pancreatic cancer researchers at Thomas Jefferson University have shown, for the first time, that blocking a receptor of a key hormone in the renin-angiotensin system (RAS) reduces cancer cell growth by activating the enzyme AMPK to inhibit fatty acid synthase, the ingredients to support cell division.

With that, a new chemopreventive agent that inhibits the angiotensin II type 2 receptor—never before thought to play a role in tumor growth—could be developed to help treat one of the fastest-moving cancers that has a 5-year survival rate of only 5 percent.

Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University and the co-director of the Jefferson Pancreatic, Biliary and Related Cancers Center, and her fellow researchers, including the chair of the Department of Surgery at Jefferson, Charles J. Yeo, M.D., FACS, present their findings in the August issue of Surgery.

Angiotensin II (AngII) is the principal hormone in the RAS that regulates our blood pressure and water balance; it has two receptors: type 1 and type 2. AngII is also generated actively in the pancreas and has been shown to be involved in tumor angiogenesis.

Previous studies have pointed to the hormone’s type 1 receptor as the culprit in cancer cell proliferation and tumor inflammation; however, the idea that type 2 had any effect was never entertained.

By looking at pancreatic ductal adenocarcinoma (PDA) cells in vitro, Jefferson researchers discovered that the type 2 receptor, not just type 1, mediates the production of fatty acid synthase (FAS), which has been shown to supply the cell wall ingredients necessary for cancer cells to multiply.

FAS was previously identified as a possible oncogene in the 1980s. It is up-regulated in breast cancers and is indicator of poor prognosis, and thus believed to be a worthwhile chemopreventive target.

“AngII is not just involved in cell inflammation and angiogenesis; it’s involved in tumor metabolism as well,” said Dr. Arafat, a member of the Kimmel Cancer Center at Jefferson. “It promotes FAS with both receptors, which makes the tumor grow.”

“Blocking the type 2 receptor reduces PDA cell growth with the activation of AMPK, revealing a new mechanism by which chemoprevention can exploit,” she added. “In fact, maybe combined blocking of the two receptors would be more efficient than just blocking one receptor.”

AMPK, or adenosine monophosphate-activated protein kinase, is the focus of several agents today, including ones for diabetes and related metabolic diseases. It is a master metabolic regulator for cells that is activated in times of reduced energy availability, like starvation. Activation of AMPK has been shown to improve energy homeostasis, lipid profile and blood pressure. The enzyme also activates a well-known tumor suppressor, p53.

“The main thing is activation of AMPK in tumor cells,” said Dr. Arafat. “AMPK is the perfect candidate as it regulates multiple targets that both halt tumor cell division and activate programmed cell death. Although it is yet to be determined how the type 2 receptor imposes deregulation of AMPK activity, identification of the type 2 receptor as a novel target for therapy is very exciting”

Next, Dr. Arafat and fellow researchers are proposing to take this research into animal studies. They hope to target the receptors early on in the disease to better understand its prevention capabilities and also study its treatment potential. Considering pancreatic cancer is typically detected in later stages, finding better ways to treat cases that have progressed further along would be of great benefit to patients.



Dr. Karen Knudsen Receives Ron Ross Award

Dr. Karen Knudsen

See the Award Announcement for more information about the Award and its latest recipient. The following was abstracted from the announcement.

Dr. Karen Knudsen of the Kimmel Cancer Center received the Ron Ross Award at the 5th Pacific Rim Breast and Prostate Cancer Meeting, held in Kingscliff, Australia, May 3-7, 2011. Dr. Ron Ross was the Flora L. Thornton Chairman of Preventive Medicine and the Catherine and Joseph Aresty Professor of Preventive Medicine and Urology at the Keck School of Medicine of the University of Southern California. Under his leadership, the Department of Preventive Medicine became the leading department in this field in the United States. Ron was also Director of the Los Angeles Cancer Surveillance Program, the cancer registry of Los Angeles County, from 1987. A respected pioneer in research on the relationship between hormones and cancer, Ron died of brain cancer on April 21 2006 at the age of 57. The Ron Ross Award acknowledges Ron’s remarkable contribution in the field of hormonal carcinogenesis and also recognizes significant contributions by others in the field.

This year’s Award was presented to Professor Karen E Knudsen from the Kimmel Cancer Center, Thomas Jefferson University. Her postdoctoral studies focused on the cross talk between androgen receptor signaling and proliferative control mechanisms in prostate cancer, and she was first to discover that interplay between hormone receptor networks and the cell cycle machinery is frequently perturbed in prostate cancer, and promotes loss of proliferative control. She was recruited to the NCI-designated Kimmel Cancer Center at Thomas Jefferson University in 2007, where she is a Professor of Cancer Biology, Urology, and Radiation Oncology. Recent pivotal findings from her group relate to critical co-factors that drive castrate resistant prostate cancer, novel therapeutic targets for treatment, and intricate mechanisms which impinge on androgen receptor function that contribute to the lethality of disease. Most recently, her group has provided seminal evidence that the retinoblastoma tumor suppressor pathway plays a critical role in the progression of prostate cancer that could be exploited to more efficiently treat advanced disease.



Dr. Gomella Appointed to Editorial Council for Urology Times and Mid Atlantic Representative for Scociety for Urology Chairperson and Program Directors

Dr. Leonard Gomella

Dr. Leonard Gomella

Dr. Leonard Gomella, M.D., F.A.C.S., the Bernard W. Godwin, Jr. Professor of Prostate Cancer, associate director for Clinical Affairs at the Kimmel Cancer Center (KCC) at Jefferson, and Chair of the Department of Urology at Jefferson Medical College of Thomas Jefferson University, has been appointed as a member of the Urology Times Editorial Council. He will represent the area of urologic cancer on the Editorial Council. “Dr. Gomella is an internationally recognized leader in the urologic cancer field,” said Richard R. Kerr, Urology Times editor-in-chief. “Dr. Gomella will be an excellent addition to our team of experts in urology.”

Dr. Gomella has also been elected the Mid Atlantic Section Representative to the Society for Urology Chairpersons and Program Directors. The mission of SCUCPD is to provide urology program chairpersons and program directors a forum for the discussion, review and implementation of issues critical to the conduct of urologic residency programs and academic practice for the purpose of advancing academic urology to the highest state of innovation resourcefulness and preparation in urologic practice and training of urologists of the future.

For this and more news from the Department of Urology at Thomas Jefferson University please see the 2010 edition of the newsletter



Marker Identifies Breast Cancer Patients Likely to Respond to Tamoxifen

Dr. Hallgeir Rui


ER positive breast cancer patients whose tumors have active protein Stat5 have increased likelihood of responding to anti-estrogen therapy

PHILADELPHIA—Cancer researchers at the Kimmel Cancer Center at Jefferson and an international team of collaborators have discovered a biomarker in breast cancer that may help identify which women will respond to anti-estrogen therapy.

The research appears in the May 16 online issue of the Journal of Clinical Oncology.

Anti-estrogen drugs, most notably tamoxifen, are widely used in patients diagnosed with estrogen receptor-positive breast cancer.  However, as many as a third of the women given tamoxifen fail to respond.

In this new study, the investigators found that women whose tumors retain the active form of the protein biomarker Stat5 have an increased likelihood of responding to tamoxifen.  In contrast, women treated with tamoxifen whose tumors lacked active Stat5 had up to a 20-fold increased risk of dying from breast cancer after adjustment for effects of standard hormone receptor markers and other pathology data.

“Identification of predictive biomarkers present in breast cancer will lead to improved individualized therapies tailored specifically towards each woman’s cancer,” said Hallgeir Rui, M.D., Ph.D., professor of oncology, Kimmel Cancer Center at Thomas Jefferson University, and principal investigator of the study.  “Absence of the active form of Stat5 could help identify a group of patients unlikely to respond to tamoxifen so they may be offered alternative and more aggressive treatments.”
Read more…



“Longevity” Protein SIRT1 May Ward Off Precursor to Prostate Cancer

Dr. Richard G. Pestell

Dr. Richard G. Pestell

Researchers from the Kimmel Cancer Center at Jefferson and two other institutions have discovered new evidence that suggests the “longevity” protein SIRT1, known for its life-spanning effects in different species, can inhibit the development of a known precursor to prostate cancer, prostatic intraepithelial neoplasia (PIN).

“Prostate cancer is one of the malignancies that has a very direct relationship to aging,” says Richard G. Pestell, M.D., Ph.D., Director, Kimmel Cancer Center and Chairman of Cancer Biology at Thomas Jefferson University. “And these results provide a direct link for the first time between the onset of prostate cancer and the Sirt1 gene that regulate aging.”

The findings were reported in the February 2011 edition of Cancer Research ( pubmed)  ( JeffNews )




Loss of the retinoblastoma tumor suppressor pushes prostate cancer into lethal stage, say Kimmel Cancer Center researchers

Dr. Karen Knudsen

Dr. Karen Knudsen

Their study, the first to uncover a new role for this powerful gene, may lead to clinical “barcoding” of a patient’s prostate cancer to help direct therapy

(PHILADELPHIA) – The retinoblastoma tumor suppressor gene (Rb), long thought to protect cells against cancer development, appears to play a very different role in prostate cancer, say scientists at the Kimmel Cancer Center at Thomas Jefferson University.  As reported today, disruption of this gene now appears to be a major factor contributing to therapeutic failure.

Read more…



“How & Why” Cancer Cells Eat Us Alive

Four key studies now propose a new theory about how cancer cells grow and survive, allowing researchers to design better diagnostics and therapies to target high-risk cancer patients.  These studies were conducted by a large team of researchers at Thomas Jefferson University’s Kimmel Cancer Center.
Read more…



Dr. Leonard G. Gomella Studies the Effect of Dutasteride on the Risk of Prostate Cancer

GomellaLeonardG

Dr. Leonard G. Gomella

Dr. Leonard G. Gomella and colleagues conducted a landmark international
randomized, double-blind, placebo-controlled, parallel-group multi-center
clinical trial to determine whether dutasteride reduces the risk of incident
prostate cancer, as detected on biopsy, among men who are at increased risk for
the disease. Over the course of the 4-year study period, dutasteride reduced
the risk of incident prostate cancer detected on biopsy and improved the
outcomes related to benign prostatic hyperplasia. These results were published
in the New England Journal of Medicine on April 1, 2010 ( Pubmed Abstract ).