Study Evaluating Toxicity & Efficacy of Lenalidomide(Revlimid®)in Chemotherapy-Naïve AIPC Patients

The standard of care in patients with androgen independent prostate cancer (AIPC) is debated. Systemic chemotherapy has shown a survival advantage with a Taxotere-based regimen, but this therapeutic approach is associated with significant toxicity and morbidity. Furthermore, some patients with AIPC are asymptomatic with minimal disease burden making systemic chemotherapy a less attractive option. Identifying active agents that are effective in this patient population is of vital importance, as this may delay the need to chemotherapy, palliate symptoms, delay progression, and potentially prolong survival. Acceptable approaches in this setting include vaccine therapies, targeted agents, immunotherapy, or non-taxotere based chemotherapeutic programs. Targeted therapy is of particular interest as this usually avoids side effects of chemotherapy by attacking tumor cells and sparing normal tissue. Ongoing research continues to identify pathways by which the prostate cancer cells become refractory to androgen blockade. During the development of prostate cancer, cell survival depends primarily on the androgen receptor, which is bound to heat shock proteins in the cytoplasm. The active metabolite of testosterone, namely dihydrotestosterone (DHT) binds to the receptor relocating it to the nucleus where it dimerizes, activating transcription genes that are involved in the growth and survival of the cancer cell. Plausible etiologies for the development of hormone resistance and continued cell growth despite adequate castration include changes in antigen receptor expression, changes in the receptor structure, and changes in androgen receptor function with more than one mechanism contributing to this resistance. Several investigators have shown that the androgen receptor gene is the only gene that is consistently up regulated during tumor progression. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from hormone-sensitive to hormone-refractory, and was dependent on a functional ligand-binding domain. Consequently, one can divide mechanisms of androgen resistance into those that involve the androgen receptor and those that do not.Pathways involving the androgen receptor allow for prostate cancer progression through amplification or mutations of the receptor, deregulation of growth factors or cytokines, and alteration of activators. Amplification of the androgen receptor gene leads to enhanced activation of that receptor even at lower levels of androgens. In addition, mutations in the receptor gene allow for activation of the receptor by different ligands. Peptide growth factors, such as insulin-like growth factor, keratinocyte growth factor, epidermal growth factor, and interleukin-6 (IL 6) can activate the antigen receptor independent of androgens.Deregulation of the apoptotic genes is another important pathway in AIPC development. PTEN tumor suppressor gene (Phosphatase and Tensin Homologue) is mutated in AIPC allowing for the loss of the inhibitory effect that it usually exhibits on the phosphatidylinositol 3-kinase pathway, causing overproduction of akt allowing for cell survival to continue. Another deregulated proapoptotic oncogene, namely bcl-2 allows for cell survival and eventually progression of disease. It has been postulated for years that tumors need an alternative source of nutrients once they outgrow their own supply. Folkman suggested that an angiogenic switch takes place, which accelerates tumor proliferation. Inhibiting tumor proangiogenic factors without affecting normal vasculature has become an attractive theory to inhibit tumor growth. Since prostate cancer, like other malignancies, require blood vessel formation to develop metastases, finding methods that would disrupt this process became of paramount importance. Two separate studies have shown that elevated levels of the vascular endothelial growth factor (VEGF) correspond with advanced stage, progression, and poor survival in prostate cancer. Since VEGF is a major regulator of angiogenesis; a process that is increased in AIPC and since VEGF also correlates with increased microvessel density as well as prognosis, a logical step was to evaluate the activity of VEGF inhibitors and other anti-angiogenesis agents in AIPC. Lenalidomide (Revlimid®) is an analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. The fact that AIPC depends on angiogenesis and lack of appropriate immune reaction to malignant cells and the fact that Revlimid® exhibits its activity by inhibiting angiogenesis with appropriate immunomodulation, makes this agent an attractive option to study in this disease setting.Several investigations suggested activity with thalidomide in AIPC but most studies were in patients who have failed systemic chemotherapy. In addition, Revlimid® has been shown in phase I trials to be safe, less toxic and more tolerable than Thalidomide, with potential activity. This study aims at evaluating the toxicity and efficacy of Revlimid® in AIPC patients who are chemotherapy-naive.