In North America, one in ten men is diagnosed with prostate cancer. Hormonal therapy, developed more than fifty years ago, is initially successful in 85-90% of patients; however, metastatic prostate cancer patients eventually develop resistance to this androgen withdrawal therapy. Further, the lack of appropriate animal models has been a major impediment to understanding the mechanism(s) responsible for the development of prostate cancer and tumor progression.
Our research focuses on the androgen regulated probasin gene which is expressed specifically in the prostate. The probasin promoter targets transgene expression to the prostate in transgenic mice and targeted oncogenes will induce prostate-specific neoplasia. We have significantly improved the efficiency of the probasin promoter by selecting precise DNA segments that result in extremely high levels of transgene expression in prostatic cells. Using these new probasin promoter constructs to target oncogenes, we can reproducibly and rapidly develop neoplasia in the prostate of transgenic mice. This has created a new animal model for prostate cancer that reproduces the full spectrum of transformation seen in human prostate disease including benign hyperplasia, pre neoplastic lesions, local invasive carcinoma, androgen-dependent cancer and progression to androgen-independent cancer. The information gained from our animal models is complemented by our human prostatic tissue acquisition program which assists in the translation of these basic research findings to the analysis of patient samples.
By identifying the factors that control prostate-specific gene expression, we will gain insight into the appearance and growth of the prostate during development of the urogenital sinus. We have developed transgenic animal models that permit us to unravel pre-natal and post-pubertal development of the prostate. The same factors that control prostate organogenesis will be required for prostate cell survival and thus will serve as unique targets to kill prostatic cancer cells.
Our basic scientific discovery that the probasin promoter directs prostate-specific gene expression is being translated into a clinical application by developing an efficient gene therapy delivery system for the treatment of prostate cancer. Our gene therapy strategy uses a probasin-directed retroviral which will precisely target a therapeutic gene only to prostate cancer cells. This reduces the toxicity of the therapeutic gene to non-prostatic cells and increases the effective dose of the therapeutic gene which in turn induces tumor regression.
Prostatic disease causes a declining quality of life and significant mortality among the aging male population. The significant impact of prostate cancer requires that we increase our basic understanding of this disease process and expand our options for effective therapy. Our overall goal is to provide a new strategy in the treatment of prostate cancer.
The research interests of this laboratory lie in understanding the relationships between the various cell types which comprise developing and adult prostate and the ways in which these relationships change in benign and malignant disease. We have been particularly interested in producing in vivo model systems, which utilize human cells. We can really only begin to understand the biology of cancer in a “whole organism” context and thus in vivo models are absolutely essential for research efforts to progress. Stromal-epithelial interactions are central determinants of organogenesis, development, and growth quiescence in adulthood. Increasing evidence demonstrates that such interactions also play a pivotal role in cancer progression. Stomal cells surrounding prostate tumors (carcinoma associated fibroblasts) act to promote the growth of cancer foci and, we have recently shown, elicit characteristic genetic changes in tumor epithelial cells. The mechanism by which such changes occur is at present unknown. One of the long term aims of this laboratory is to understand the nature of these interactions and thus identify targets which direct therapy at the genetically normal stromal compartment of the affected organ rather than at the moving target of the tumor epithelium. This brings the prospect of perhaps restraining tumor growth and turning cancer into a chronic but treatable disease.
Major basic research projects in the laboratory examine: the role of transforming growth factor beta in benign and malignant prostatic disease, and; the role that stromal signaling, in particular growth factor mediated signaling, in cancer progression as well as approaches to inhibit this effect. We are also interested in pursuing translational research with pharmacogenomic projects to identify gene and protein profiles which predict the ability of individual tumors to either respond, or fail to respond, to specific chemotherapeutic agents. The aim of these projects is to identify the patients most, and least, likely to benefit from specific therapeutic options and thus to optimize therapies on an individual basis.
One focus of the Bhowmick lab is to understand the mechanism of cell-cell communication. We are specifically interested in 1) the interactions that involve signaling molecules secreted from stromal cells that elicit a response in the neighboring cell - paracrine signaling and 2) the subsequent cytoplasmic signals that dictate cell proliferation or differentiation. We hypothesize that alteration of such communication is not only coincident with transformation and cancer progression, but can in fact be a causative mechanism of tumorigenesis. We have developed conditional knockout mice that ablate transforming growth factor-beta (TGF-ß) signaling in stromal fibroblasts. These mice spontaneously develop lesions resembling human prostate intraepithelial neoplasia. Thus TGF-ß signaling pathway, known to directly inhibit normal epithelial cell proliferation, can also indirectly inhibit epithelial proliferation when activated in adjacent stromal fibroblasts. We are in the process of identifying paracrine and autocrine signaling mechanisms associated with this process with the goal of targeting the cancer stroma as a viable target for potential therapies.
The other focus of the Bhowmick lab is mining for biomarkers that can be used for early detection of prostate cancer, bladder cancer, and renal cancer. The fact that there has been little change in the mortality figures in the past 20 years for these specific urogenital cancer suggest the current limitations of cancer early detection. We are using a strategy based on MALDI-mass spectrometry and recombinant single-chain antibody to identify peptides found in urine to provide diagnostic markers for prostate, bladder, and renal cancer. To move beyond the exploratory stage, sufficient numbers of patient samples with associated clinical data, an efficient validation technique, and substantial statistical input will be employed in these studies.
Advanced renal cell carcinoma (RCC) remains a challenging disease to treat effectively given its resistance to traditional chemotherapeutic approaches. Recent advances in targeted therapies have dramatically changed the paradigm for managing this disease, however these approaches tend to produce stable disease or partial responses, whereas complete eradication of disease (or “cure”) remains exceedingly rare. We cannot afford to become complacent and assume we have won the battle against advanced RCC. New and innovative approaches to treating this disease are still critically needed.
Apo2 ligand/Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is one of a family of ligands (including TNFa and Fas/CD95 ligand) that can induce programmed cell death, or apoptosis, by binding to cell surface death receptors. TRAIL is particularly relevant to cancer therapeutics since it has been found to preferentially induce apoptosis in malignant or transformed cells while sparing normal cells. This makes it a potentially powerful tool in treating a variety of malignancies. Indeed, TRAIL related therapeutics are in early clinical trials in patients with advanced malignancies. The focus of my lab is to better understand the mechanisms of TRAIL mediated apoptosis in genitourinary malignancies with a strong emphasis on RCC. There are several ongoing projects in the lab.
For many years interferon alpha (IFNa) was a mainstay of therapy for advanced RCC. IFNa is known to modulate TRAIL mediated apoptosis in a variety of cell types. Our work has shown that IFNa and TRAIL can act synergistically to induce cell death in RCC cells representing a potentially powerful approach to treating RCC. We are actively investigating the molecular mechanisms underlying this synergy.
We are constructing a 300 patient, annotated tissue micro-array of RCC tumor tissue with matching normal kidney parenchyma with long term patient follow up and extensive linked clinical data. Once constructed, we plan to use this to test the prognostic significance of changes in a variety of molecular markers in patients with RCC. The first planned markers will be TRAIL and its cognate Death Receptors, with more planned depending on the findings from our other work.
We are are developing new, innovative genetic mouse tumor models of kidney cancer in an effort to provide better tools for screening and developing novel therapeutics. In the process we are exploring the role of oncogenic Ras in renal function and development.
These studies will help delineate the mechanisms of TRAIL mediated apoptosis in RCC and better define its potential role as a therapeutic in this disease.