BCM researchers leading efforts in bladder cancer research
Find out more about important advances in drug development, new theories about bladder cancer stem cells and the biology of the bladder from BCM researchers Dr. Guru Sonpavde, clinical assistant professor of medicine – hematology and oncology, Dr. Keith Syson Chan, assistant professor of urology and of molecular and cellular biology, Dr. Carolyn Smith, assistant professor of molecular and cellular biology and Dr. Seth Lerner, professor of urology.
There are a host of drugs, new and old, being studied as potential treatments for bladder cancer. Sonpavde is involved in a variety of clinical and laboratory trials that have tested a host of new therapies.
"Advanced stage metastatic bladder cancer (muscle invading) is generally not curable with currently available chemotherapy," said Sonpavde. "We really need to improve upon the standard approach to treatment of muscle-invading bladder cancer still confined to the bladder, which typically includes the removal of the bladder and some form of chemotherapy with radiation for those unable to undergo bladder removal surgery."
Sonpavde outlined some of the lab and clinical work he has been involved with at BCM.
In one lab-based study, BCM researchers focused on a drug called Sutent, already approved by the U.S. Food and Drug Administration for advanced kidney and gastrointestinal cancers. In the bladder cancer model, the drug was shown to block tumor cell growth by inhibiting certain cell signaling pathways that promote blood vessel growth. "Basically, this ‘anti-angiogenic treatment' slowed down the cancer cell division," said Sonpavde.
The team has also studied a drug called Sprycel, already approved by the FDA for the treatment of chronic myeloid leukemia. Also a cell signaling inhibitor, in the bladder cancer model, the drug targets a tumor growth-promoting molecule called SRC. "We found that the inhibition of SRC signaling activity in a type of cancer that over-expressed SRC slowed growth of cancer with this drug."
Sonpavde and his research team recently received funding for a laboratory bladder cancer study from Cephalon, a company developing a new drug called CEP-11981. The compound inhibits angiogenesis (the formation of new blood vessels).
He also obtained support and funding from Celgene to study lenalidomide (Revlimid) in a laboratory bladder cancer model. This drug is FDA approved for multiple myeloma and myelodysplastic syndromes and appears to work by inhibiting blood vessel growth, as well as promoting the immune system.
In one clinical trial Sonpavde calls a "window of opportunity," the team is studying the effect of Sprycel in the neoadjuvant setting – chemotherapy or radiation given to patients prior to surgery. The trial will involve patients waiting for a cystectomy (removal of the bladder) to see if the drug can block some tumor growth promoting signaling pathways. "This is a new design," said Sonpavde. "These patients would otherwise have been waiting for surgery for three, sometimes four weeks without drug activity."
In other clinical trials, the researchers are looking at a new combination including chemotherapy plus Sutent prior to cystectomy, and studying the effect of Tamoxifen (an estrogen receptor) for metastatic bladder cancer that continues growing after previous chemotherapy. Tamoxifen has previously been approved for breast cancer and showed promising activity in the bladder cancer animal models in Drs. Lerner, Sonpavde and Smith's laboratory.
"These are new designs that hold a lot of promise for future treatment of the disease," said Sonpavde. "We hope to have exciting new contributions for the field."
Additionally, Sonpavde is involved in studying the natural history of bladder cancer after surgery to remove the bladder cancer. Such studies of large numbers of patients will help identify patients with a higher risk of future recurrence of cancer that might require more aggressive therapy following surgery.
The study of cancer stem cells, the cells that are resistant to conventional therapies (chemotherapy, radiation) is an emerging area of research. Chan has focused his research on a promising new theory regarding cancer stem cells. Chan and his team have isolated bladder cancer stem cells and are studying how to better attack them and improve targeted therapy.
"Non-invasive bladder cancer is quite curable," said Chan. "But 15 percent of these cases will progress to invasive cancer. We currently have no good clinical or prognostic markers for predicting this progression."
Using invasive bladder cancer tumor samples, cancer stem cells are isolated following removal of the bladder. "We hypothesize that though a large portion of the cancer was removed, the tumor-initiating cells will prompt recurrence and metastasis."
Chan and his team performed a genetic analysis on cancer stem cells and found a gene signature that can separate invasive from non-invasive cancer. "If the cancer stem cell signature is present in patients with non-invasive, then we have a good signature for predicting those that will become invasive."
The team has also identified a protein CD47 that is highly expressed in cancer stem cells.
"This protein is an inhibitory or ‘don't eat me' signal on cancer cells for immune cell macrophages, or cells that are able to engulf foreign materials," said Chan. "When this protein is blocked by an antibody, the can eat the cancer cells."
Chan said the research is significant because preclinical results using this antibody led to slow down of tumor growth.
In addition to looking at what is happening inside the cells, Chan and his team are looking at the tumor microenvironment. "There are certain factors in the microenvironment that support these cells," said Chan. "We are seeking to understand what those are."
Understanding the biology of the bladder
Smith and her team focus on another area they believe may unlock clues about the overall biology of the human bladder – the role of estrogen receptors.
Estrogen receptors are proteins that estrogen binds to. Estrogens are sex steroids present in males and females that stimulate the development and maintenance of many different tissues.
"There are two forms of estrogen receptors – alpha and beta," said Smith. "We found that estrogen receptor beta was expressed in human bladder tumors." Very little alpha was found.
The direction of this research is significant because researchers believe they could use this form of estrogen receptor as a target to control the growth of bladder cancer cells.
In experiments with bladder cancer cells, as well as animal models, the team has shown that estrogen receptor inhibitors (anti-estrogens) slow the growth of bladder cancer cells.
Smith and her team have also collected similar results in a cancer prevention model. "The recurrence rate of bladder cancer is high and there is a strong need to develop additional approaches to stopping this cancer from coming back."
Using selective estrogen receptor modulators, or SERMS, the researchers can block estrogen receptor action in certain parts of the body.
"From a pharmacologic perspective, this class of drugs is very interesting and holds a lot of promise for research," said Smith. "They do not inhibit estrogen action everywhere in the body – for example, men and women need estrogen to keep their bones protected – but are effective in specific organs."
In this case, the bladder, Smith said.
"We are very interested in better defining the role of estrogen receptors in the biology of the bladder," said Smith. "We want to know how they work in normal bladder and bladder cancer, and how to best target the receptors to block bladder cancer development and growth."