Cholesterol Synthesis and Statin Therapy in Prostate Cancer
Abstract
Rationale: New data suggests that prostate cancers are more deadly if they produce more cholesterol themselves. Cholesterol, a building block of cell membranes and hormones, is necessary for prostate cancer development and progression. Cancer cells also use cholesterol to make androgen hormones, which fuel prostate cancer progression further. Key steps of cholesterol production rely on the enzymes HMGCR and SQLE. In a study of 740 prostate cancer patients, we demonstrated that patients who had cancers containing high amounts of mRNA for SQLE were much more likely to die from their cancer or develop metastases. Our research indicates that active cholesterol production may counteract androgen deprivation therapy (ADT), which is commonly used to slow prostate cancer. The results suggest that cholesterol production within a cancer could be a valuable indicator of both progression to lethal disease, despite radical surgery, and responsiveness to ADT. Being able to easily gauge how active an individual patient’s tumor is in making cholesterol could help reduce both under- and over-treatment of prostate cancer patients. It may help identifying, at the time of cancer diagnosis, who is likely to benefit from additional therapy right away beyond what is currently recommended. In contrast to many other investigated mechanisms of cancer progression, there is an approved class of medications that blocks cholesterol production in tumors. These medications, statin pills such as atorvastatin, rosuvastatin, or simvastatin, are used by millions of patients to lower cholesterol levels. They have quite limited side effects compared to typical cancer medications. Observational studies have suggested that prostate cancer is less likely to progress if patients take a statin for another reason. To convince physicians and patients to use statins for prostate cancer treatment, randomized-controlled trials (RCTs) of statins for prostate cancer patients have been initiated. However, as we revealed, only a subgroup of patients have cancers that are very active in producing cholesterol. Because of that, it is unlikely that all prostate cancer patients will benefit from statins. Thus, we first need to identify exactly those patients who have the best chance of benefitting from a statin. Objective: We aim at translating cholesterol production activity of a patients’ prostate cancer, measured by SQLE mRNA and HMGCR protein, into biomarkers. These will help identify prostate cancer patients who are at risk of cancer progression under standard treatments and patients who may benefit from statin therapy. Specific Aims: We will (1) translate HMGCR into a protein biomarker of cholesterol production to predict lethal prostate cancer; (2) evaluate whether measuring HMGCR can predict responsiveness to ADT; (3a) assess whether measuring cholesterol production (via SQLE mRNA) helps identifying patients with very aggressive forms of metastatic castration-resistant prostate cancer (mCRPC); and (3b) determine whether cholesterol production predicts which patients experience less cancer progression due to statin use. Applicability and Benefit for Patients: Findings from our study have the potential to satisfy an unmet need in the detection and prevention of lethal prostate cancer. Our results will help identify which patients have an aggressive tumor that is active in producing cholesterol and hence should be treated differently. Helping differentiate aggressive and indolent prostate cancers, our study will also identify prostate cancer patients who should be treated, not only with standard treatments, but also with statin therapy. The new biomarkers will help physicians identify, at the time of diagnosis, patients in need of extra therapy to actively prevent progression to lethal cancer. They will also help select patients who will do well without extra therapy. Statin therapy has the potential for a near-term and multidimension
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810330
Entities
People
- Konrad H Stopsack
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army