The Louis Warschaw Prostate Cancer Center utilizes established therapies, as well as leading-edge clinical treatment protocols derived from our basic, pre-clinical laboratory research. This important combination of pre-clinical laboratory and clinical research under one roof, called translational research, narrows the gap between research and practice and brings therapies to prostate cancer patients quickly.
Currently, when one is diagnosed with localized prostate cancer, the primary therapy is either surgery or radiation therapy. These treatments do not target prostate cancer specifically and can leave the patient with major side effects. These morbidities are frequently lifelong and include pain, sexual dysfunction, incontinence, loss of self-esteem and altered body image. Yet, surgery and radiation are still the current standards of care for this disease.
No currently available therapy is able to cure prostate cancer once it has metastasized (spread outside its point of origin in the body). Hormone therapy (removal of testosterone) is the most effective therapy but will cause the cancer to stop growing only for a period of time. In all cases, the tumor will grow back. Furthermore, prostate cancer tends to metastasize to the bone, where it is difficult to measure and to treat with current methodologies.
Due to these difficulties in treating advanced prostate cancer, pharmaceutical companies have been reluctant to invest in costly clinical trials. Frequently, they find that the cost of FDA clearance for marketing is not justified by the poor outcomes of cancer patients after treatment with their pharmaceutical products. From the perspectives of both prostate cancer patients and pharmaceutical companies, more effective treatments will be necessary-ones that target the cancer cells specifically. Basic laboratory research is required for the development of such targeted therapies.
We are at a critical point in the history of cancer research. The data yielded by the Human Genome Project (the sequencing of all human genes) and the availability of new technologies for using these data have greatly increased our arsenal for our fight against prostate cancer. Andrew S. Grove, Chairman of the Board of Intel Corporation, speaks of a phenomenon that occurs in industry termed an "inflection point." This phenomenon occurs when large advances in technology cause a change in the slope of the curve of progress versus. time. Those institutions that can transform and adapt to these changes will succeed at a much faster rate than those who fail to adapt. We are at such an inflection point in the progress of prostate cancer research. Success in cancer research translates to lives saved.
Cancer is not one disease. It is a multitude of diseases, each of which has its origin at the molecular level. Cancer is the result of one or more genetic mutations that cause cells to grow and divide abnormally. Many different types of mutations can result in a cell becoming cancerous. Even among cancers of a particular organ, such as the prostate, every patient's cancer has different characteristics. When certain molecular mechanisms go awry, the cell acquires different growth characteristics. As these cells lose their differentiation, they may be able to metastasize (spread) to other sites in the body, causing trouble there as well.
Normal prostate cells are dependent on androgens (hormones) for growth. Prostate cancer cells may start as androgen-dependent cells and as the cancer progresses, can transform to become androgen-independent, giving rise to hormone-refractory prostate cancer (HRPC). This change in hormone dependency usually makes for a poor prognosis for the patient, and treatment of HRPC is usually ineffective.
The tools of molecular biology can guide the development of treatments for cancer. The sequencing of the human genome and the advent of new technologies allow data to be queried from an individual's cancer for the purpose of identifying the dominant "on" pathways. The goal in cancer research is to learn how to turn such pathways "off" or to destroy cells in which these pathways are turned "on." In the laboratory, molecules are synthesized with the goal of targeting these pathways.
In the last several years, the biotechnology and pharmaceutical industry has focused on this area of targeted therapy. Frequently, the changes that occur in cancer cells include an increased presence of specific receptor molecules on their cell surface with the consequence of turning on a molecular pathway. In the laboratory, either monoclonal antibodies or small molecules can be produced to target these receptors selectively and to destroy these receptor-bearing cells or to interfere with the molecular pathways of the cells that afford their aberrant growth.
Human epidermal receptor-2 (HER-2) is an "on" switch in prostate cancer. It is part of a tyrosine kinase receptor system that is located in the membranes of prostate cells. HER-2 binds other cell surface receptors, including the epidermal growth factor receptor (EGFR; HER-1), HER-3 and HER-4 (the other members of the HER-kinase family of receptors) to form a dimer (two molecules bound together), which can then signal the cell. When molecules outside of the cell, called ligands, bind to Her-kinase receptors, they trigger a chain of biochemical events that affects the prostate cell, causing it to grow and proliferate.
In order to study the molecular pathways that are important in prostate cancer, biologists use experimental models of prostate cancer in the laboratory. These models include tumor cell lines, which are cancer cells that are grown in culture, as well as xenograft models, which are mice that have human prostate tumors implanted under their skin. Xenograft models are made possible by using mice that are genetically engineered to have no immune system and to accept the tumor implantation. These mice are termed "nude" because in knocking out the gene for their immune system, the gene for hair growth is also knocked out, giving rise to mice without hair. By studying these experimental models, the Agus Lab of the Prostate Cancer Center has demonstrated that the HER-2 is an important part of the HER-kinase pathway.
2C4 is a monoclonal antibody that binds selectively to HER-2. Scientists at Genentech, Inc., have developed this antibody and have worked with the Agus Lab to develop it into a therapy for cancer. Scientists here at the Prostate Cancer Center have found that 2C4 turns off the HER-kinase pathway in xenograft models. 2C4 inhibits the growth of prostate cancer cells that are androgen dependent and also in cells that have lost this androgen dependency. This finding with 2C4 in the laboratory offers a promising prospect for the use of 2C4 in prostate cancer patients, especially those individuals with HRPC. The Agus Lab has found similar data in xenograft models of breast cancer.
Frequently, monoclonal antibodies work better when used in conjunction with a chemotherapeutic agent. 2C4 plus the chemotherapeutic agent paclitaxel (Taxol) produces greater growth inhibition when applied to both androgen-dependent and androgen-independent prostate cancer cells than when either agent is used alone. This finding shows promise for the combined use of these two agents in clinical practice. These data have been presented at several national meetings and have been published in scientific journals. Furthermore, these findings have been translated recently into a Phase-1 clinical trial in advanced cancer patients at the Prostate Cancer Center.
The Louis Warschaw Prostate Cancer Center is using knowledge acquired in the laboratory to direct the implementation of clinical trials of therapies that hold promise for prostate cancer patients. With the decision of Genentech to move forward with clinical studies of 2C4, the Prostate Cancer Center is conducting a Phase-1 clinical trial in patients with advanced cancer. This pilot study serves to test the safety of 2C4. It is not disease-specific; it includes patients with prostate cancer, as well as other cancer types. The first dosage of 2C4 was administered to a patient at Cedars-Sinai Medical Center in October 2001. Once we have demonstrated the safety and efficacy of 2C4 in these patients, Phase-II trials will begin in patients with prostate cancer in the third quarter of 2002.
The primary goal of the Louis Warschaw Prostate Cancer Center is to quickly bring more effective and targeted therapies to the prostate cancer patient from the laboratory. We are committed to collaborating with the "best of breed" to work towards this end.
