Below is a press releases from last week [1].
{A cell/mouse study was actually published in 2015 [2].}
Cholesterol accumulation is something that occurs in tumor cells, a fact that was noted a hundred years ago. In PCa, the accumulation is associated with aggressiveness. Enough reason, I think, to consider a statin, regardless of what one's LDL status is.
Cholesterol is of particular significance in PCa, since treatments mostly entail depriving the cancer of androgens, & cholesterol is the starting point for steroidogenesis. Not only can PCa cells use their cholesterol to make androgen, but the cells are also capable of making cholesterol.
Examination of the Wiki-pages for Zytiga & Xtandi informs one that the drugs are used to treat metastatic castration-resistant prostate cancer. i.e. first we close the largest barn door, then we move on to the next & so on. Dr. Myers has spoken against the sequential approach, claiming that successful treatments for other forms of cancer all require more that one drug.
In any event, I tend to think of the cholesterol problem as being the last ADT barn door. When all other doors have been closed, the cells will synthesize cholesterol & find a pathway to create androgen.
The Purdue University technology licensed by Resarci Therapeutics targets cholesterol metabolism.
""We target the aberrant cholesterol metabolism using an inhibitor of cholesterol esterification enzyme ACAT-1, named avasimibe. Avasimibe selectively kills cancer cells by preventing the cholesteryl ester accumulation and inducing free cholesterol related toxicity in cancer cells.""
"... the company has demonstrated the ability of the inhibitor avasimibe to overcome the resistance to hormone therapy in mouse models and is looking to further improve their product in future trials."
Unfortunately, while cholesterol synthesis & metabolism may be the final ADT barn door, treatment may select for androgen receptor mutations that do not require androgen binding - e.g. AR-V7. i,e, where castration becomes irrelevant.
The press release is a bit misleading:
"Resarci Therapeutics has developed a new therapeutic strategy by targeting the cholesterol metabolism instead of the androgen pathway."
& yet they claim that the treatment can "overcome the resistance to hormone therapy", which suggests that they don't see ADT going away.
However, in the published study:
"In cell lines of human prostate, pancreatic, lung, and colon cancer, avasimin significantly reduced cholesteryl ester storage in lipid droplets and elevated intracellular free cholesterol levels, which led to apoptosis and suppression of proliferation."
Which makes it clear that they view the drug as having potential for all solid tumors that accumulate cholesterol. If that works, we might finally move out of the Huggins castration era.
In fact, back in May, it was touted as a treatment for pancreatic cancer [3].
-Patrick
[1] medicalxpress.com/news/2016...
Startup develops late-stage prostate cancer therapy that could increase patient survival rates
October 13, 2016
Startup develops late-stage prostate cancer therapy that could increase patient survival rates
Junjie Li, a postdoc research fellow in the Weldon School of Biomedical Engineering, retrieves a sample that will be tested for research related to the development of an alternative therapy for late-stage prostate cancer patients who may …more
A biomedical startup that licensed a Purdue University technology has developed a late-stage prostate cancer therapy that could provide an alternative to current hormone therapies that are known to develop resistance after prolonged use.
Ji-Xin Cheng, a professor in Purdue's Weldon School of Biomedical Engineering; Junjie Li, a postdoc research fellow in the Weldon School of Biomedical Engineering; and Timothy L. Ratliff, a professor in Purdue's College of Veterinary Medicine and director of the Purdue University Center for Cancer Research, co-founded Resarci Therapeutics LLC to further develop the technology.
Cheng said that resistance to current hormone therapies is one of the biggest challenges patients face in treatment.
"Hormone therapies have a goal to reduce male hormones, called androgens, in the body, or to stop them from affecting prostate cancer cells," he said. "Almost 100 percent of cancer patients will eventually develop a resistance to hormone therapies. Every year in the United States around 32,000 new cancer cases become resistant, lessening the likelihood of survival."
Resarci Therapeutics has developed a new therapeutic strategy by targeting the cholesterol metabolism instead of the androgen pathway.
"By targeting the cholesterol metabolism, which is specific to cancer cells and independent of the hormone signaling pathway, we are able to eliminate the hormone resistance," Li said. "We target the aberrant cholesterol metabolism using an inhibitor of cholesterol esterification enzyme ACAT-1, named avasimibe. Avasimibe selectively kills cancer cells by preventing the cholesteryl ester accumulation and inducing free cholesterol related toxicity in cancer cells."
Ratliff said the company has demonstrated the ability of the inhibitor avasimibe to overcome the resistance to hormone therapy in mouse models and is looking to further improve their product in future trials.
"We want to improve the formulation of our product, test it in preclinical settings and launch an early-stage clinical trial," he said. "We are applying for funding from NIH and other agencies but are also looking for investors or potential partnerships with pharmaceutical companies."
[2] ncbi.nlm.nih.gov/pubmed/?te...
ACS Nano. 2015 Mar 24;9(3):2420-32. doi: 10.1021/nn504025a. Epub 2015 Feb 16.
Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment.
Lee SS1, Li J1, Tai JN1, Ratliff TL1, Park K1, Cheng JX1.
Author information
Abstract
Undesirable side effects remain a significant challenge in cancer chemotherapy. Here we report a strategy for cancer-selective chemotherapy by blocking acyl-CoA cholesterol acyltransferase-1 (ACAT-1)-mediated cholesterol esterification. To efficiently block cholesterol esterification in cancer in vivo, we developed a systemically injectable nanoformulation of avasimibe (a potent ACAT-1 inhibitor), called avasimin. In cell lines of human prostate, pancreatic, lung, and colon cancer, avasimin significantly reduced cholesteryl ester storage in lipid droplets and elevated intracellular free cholesterol levels, which led to apoptosis and suppression of proliferation. In xenograft models of prostate cancer and colon cancer, intravenous administration of avasimin caused the concentration of avasimibe in tumors to be 4-fold higher than the IC50 value. Systemic treatment of avasimin notably suppressed tumor growth in mice and extended the length of survival time. No adverse effects of avasimin to normal cells and organs were observed. Together, this study provides an effective approach for selective cancer chemotherapy by targeting altered cholesterol metabolism of cancer cells.
KEYWORDS:
ACAT-1 inhibitor; avasimibe; cancer; cholesterol; cholesteryl ester; human serum albumin
PMID: 25662106 DOI: 10.1021/nn504025a
[PubMed - indexed for MEDLINE]
Circulating Lipid Profiles Associated With Resistance to Androgen Deprivation Therapy in Localized Prostate Cancer
Abstract from U of Maryland by Costello & Ferguson
