Revisiting Antiangiogenic Therapy to Target Hormone-Sensitive Prostate Cancer Metabolism

项目总结

PROJECT SUMMARY In patients with advanced prostate cancer, phase III clinical trials of angiogenesis inhibitors with standard of care therapies demonstrated clear antitumor activity but failed to improve overall survival. Why some men benefited from those therapies while others did not remains unclear. Our preliminary data indicate that blockade of anaplerotic signaling pathways, which replenish metabolites syphoned from the tricarboxylic acid (TCA) cycle for rapid growth, by inhibition of CAMKK2 or glutaminase, while initially effective, invariably gives way to CAMKK2 or glutaminase inhibitor resistance. Notably, we found that a common feature of these relapsed tumors is increased angiogenesis. Indeed, analysis of patient-derived tumor specimens indicate that there exists a compensatory association between angiogenesis and anaplerotic signaling pathways, suggesting that when one process is low, the other needs to be high to sustain the tumor’s metabolic demands, with the strongest inverse association occurring in hormone-sensitive prostate cancer. The goal of this proposal is to evaluate whether co- targeting cancer cell anaplerotic metabolism and tumor angiogenesis can synergize to treat hormone-sensitive prostate cancer. We also seek to determine whether biomarkers of anaplerotic signaling can predict response to antiangiogenic therapy and therefore, guide patient selection. It is our central hypothesis that blocking angiogenesis forces cells into a state of semi-starvation that compromises anaplerosis and dramatically enhances tumor sensitivity to inhibition of central carbon metabolism. We further hypothesize that biomarkers of anaplerotic signaling can predict response to antiangiogenic therapy. We will test our hypotheses with the following aims: Aim 1 will evaluate angiogenesis as a mechanism of resistance to CAMKK2 inhibition and anaplerotic stress. We will investigate synergy between CAMKK2 and VEGF inhibition in models of hormone- sensitive prostate cancer with or without surgical castration and characterize the effects on anaplerosis using bulk and imaging mass spectrometry, as well as their impact on tumor features via MRI, histopathology, and immunohistochemistry. Aim 2 will determine if a clinical-grade inducer of anaplerotic stress sensitizes prostate cancers to the antitumor effects of antiangiogenic therapy. To further evaluate our central hypothesis, Aim 2 will determine the effects of an inhibitor of glutaminase, which also blocks anaplerosis. Aim 3 will assess whether anaplerotic signaling predicts for sensitivity to antiangiogenic therapy in patients. To do this, we will interrogate two completed, tissue-rich phase II trials that tested the presurgical efficacy of the antiangiogenic agents axitinib and sunitinib in men presenting with high-risk, very high-risk, and early metastatic prostate cancer. This research is highly significant and innovative because it will: 1) set rationale for a new form of drug combinations integrating metabolic modulators and antiangiogenics for the treatment of hormone-sensitive prostate cancer; 2) develop new candidate biomarkers to guide patient selection for clinically active angiogenesis inhibitors in treatment schemas for prostate cancer; and 3) facilitate new drug discovery efforts targeting CAMKK2.