Radiosensitizing Prostate Cancer by Downregulation of Androgen Receptors and c-Myc

DESCRIPTION provided by applicant Prostate cancer PCa is the most commonly diagnosed non cutaneous malignancy and the second leading cause of cancer related deaths in US males PCa at all stages is dependent on the activity of the androgen receptor AR and consequently targeting this pathway has been a focus for therapeutic intervention Additionally Myc is one of a few bonafide oncogenes imperative to PCa progression and aggressiveness which is often deregulated through the disease course and represents a potential but currently undruggable target for PCa Radiation therapy often combined with androgen deprivation therapy ADT is standard of care for patients presenting with organ confined or locally advanced disease and has recently been approved for treatment of metastatic disease Deregulation of AR and Myc are both implicated in decreased sensitivity to radiotherapy Therefore novel therapies that inhibit AR and or Myc signaling could effectively radiosensitize PCa cells thereby improving disease management It is well established that sphingolipid metabolism plays key roles in tumor biology In particular sphingosine kinases SK and SK are a potential site for manipulation of the ceramide sphingosine phosphate rheostat that regulates the balance between tumor cell proliferation and apoptosis as well as tumor sensitivity to radiation We and others have demonstrated that SKs are frequently overexpressed in many human cancers including PCa and that inhibition of SK activity has anti proliferative effects on tumor cells Apogee Biotechnology Corporation has identified orally available SK inhibitors with activity in vitro and in vivo The lead SK inhibitor designated as ABC has antitumor and anti inflammatory activities in several in vivo models while exhibiting minimal toxicity ABC has recently completed phase I clinical testing in patients with advanced solid tumors but has not been previously assessed in PCa patients or preclinical models We have now found that ABC effectively decreases AR and Myc expression and activity attenuates PCa cell growth and inhibits in vivo tumor growth Therefore we hypothesize that ABC can radiosensitize PCa in vitro and in vivo and significantly diminish tumor growth To support expanding clinical trials of ABC into PCa patients we will conduct studies to determine the therapeutic efficacy of ABC in in vitro and in vivo models of PCa in combination with a relevant radiotherapy regimen The following Specific Aims will be addressed in this phase SBIR project To analyze the in vitro capability of ABC to sensitize PCa cells to radiation therapy To determine the mechanism for ABC mediated radiosensitization and To evaluate the ability of ABC to modify radiation therapy for PCa in vivo Clear mechanistic rationale and extensive Preliminary Studies support the hypothesis that ABC will provide a new effective therapy for PCa that uniquely targets multiple pathways driving disease aggressiveness progression and resistance to therapy Successful completion of this project will leverage our clinical experience with ABC by providing justification to the FDA to expand our clinical trials into PCa a disease with a high unmet clinical need PUBLIC HEALTH RELEVANCE Radiation therapy is a common treatment for prostate cancer however a significant percentage of patients do not respond or develop radioresistance New drugs targeting critical pathways that drive growth and survival of prostate cancer cells in response to radiation are desperately needed Sphingolipid metabolism and sphingosine kinases in particular may play critical roles in prostate cancer We have identified a novel sphingosine kinase inhibitor that simultaneously inhibits three key pathways that promote resistance to PCa radiation therapy Here we will determine the effectiveness of this inhibitor in prostate cancer models with the goal to identify new strategies for the treatment of this disease