CRPC & 'Drug Repositioning'

[pjoshea13]

New study [1].

"The drug candidates of sorafenib, olaparib, elesclomol, tanespimycin, and ponatinib were predicted to be active for the treatment of CRPC. Meanwhile, CRPC-related genes, in this case MYL9, E2F2, APOE, and ZFP36, were identified as having gene expression data that can be reversed by these drugs. Additionally, lenalidomide in combination with pazopanib was predicted to be most potent for CRPC."

[2] Sorafenib

"(co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),[1] is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma." [2]

[3] Olaparib

"(AZD-2281, MK-7339 trade name Lynparza) is an FDA-approved targeted therapy for cancer. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers." [3]

[4] Elesclomol

"(INN, codenamed STA-4783) is a drug that triggers apoptosis (programmed cell death) in cancer cells. It is being developed by Synta Pharmaceuticals and GlaxoSmithKline as a chemotherapy adjuvant, and has received both fast track and orphan drug status from the U.S. Food and Drug Administration for the treatment of metastatic melanoma." [4]

[5] Tanespimycin

"(17-N-allylamino-17-demethoxygeldanamycin, 17-AAG) is a derivative of the antibiotic geldanamycin that is being studied in the treatment of cancer, specifically in younger patients with certain types of leukemia or solid tumors, especially kidney tumors.

"It works by inhibiting Hsp90, which is expressed in those tumors.

"It belongs to the family of drugs called antitumor antibiotics." [5]

[6a] Lenalidomide

"(trade name Revlimid) is a derivative of thalidomide approved in the United States in 2005.

"It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Along with several other drugs developed in recent years, lenalidomide has significantly improved overall survival in myeloma (which formerly carried a poor prognosis), although toxicity remains an issue for users.[2] It costs $163,381 per year for the average patient." [6a]

[6b] Pazopanib

"(trade name Votrient) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide." [6b]

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/313...

Front Oncol. 2019 Jul 23;9:661. doi: 10.3389/fonc.2019.00661. eCollection 2019.

Screening of Drug Repositioning Candidates for Castration Resistant Prostate Cancer.

Kim IW1, Kim JH1, Oh JM1.

Author information

1

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, South Korea.

Abstract

Purpose: Most prostate cancers (PCs) initially respond to androgen deprivation therapy (ADT), but eventually many PC patients develop castration resistant PC (CRPC). Currently, available drugs that have been approved for the treatment of CRPC patients are limited. Computational drug repositioning methods using public databases represent a promising and efficient tool for discovering new uses for existing drugs. The purpose of the present study is to predict drug candidates that can treat CRPC using a computational method that integrates publicly available gene expression data of tumors from CRPC patients, drug-induced gene expression data and drug response activity data. Methods: Gene expression data from tumoral and normal or benign prostate tissue samples in CRPC patients were downloaded from the Gene Expression Omnibus (GEO) and differentially expressed genes (DEGs) in CRPC were determined with a meta-signature analysis by a metaDE R package. Additionally, drug activity data were downloaded from the ChEMBL database. Furthermore, the drug-induced gene expression data were downloaded from the LINCS database. The reversal relationship between the CRPC and drug gene expression signatures as the Reverse Gene Expression Scores (RGES) were computed. Drug candidates to treat CRPC were predicted using summarized scores (sRGES). Additionally, synergic effects of drug combinations were predicted with a Target Inhibition interaction using the Minimization and Maximization Averaging (TIMMA) algorithm. Results: The drug candidates of sorafenib, olaparib, elesclomol, tanespimycin, and ponatinib were predicted to be active for the treatment of CRPC. Meanwhile, CRPC-related genes, in this case MYL9, E2F2, APOE, and ZFP36, were identified as having gene expression data that can be reversed by these drugs. Additionally, lenalidomide in combination with pazopanib was predicted to be most potent for CRPC. Conclusion: These findings support the use of a computational reversal gene expression approach to identify new drug and drug combination candidates that can be used to treat CRPC.

KEYWORDS:

castration resistant prostate cancer; drug activity; drug repositioning; gene expression; synergic effect

PMID: 31396486 PMCID: PMC6664029 DOI: 10.3389/fonc.2019.00661

***

[2] en.wikipedia.org/wiki/Soraf...

[3] en.wikipedia.org/wiki/Olaparib

[4] en.wikipedia.org/wiki/Elesc...

[5] en.wikipedia.org/wiki/Tanes...

[6a] en.wikipedia.org/wiki/Lenal...

[6b] en.wikipedia.org/wiki/Pazop...

[RICH22]

thnx for the post. lenalidomide's toxicity comes on slowly, took me about 3 months before i developed a massive really itchy rash. went off it for about 2 months, hemato-onc had me try every other day and so far, efficacious for improving anemia caused by MDS (del-5q, DNA damage). so when the casodex stops working for my PCa, i'll just add pazopanib. man, the fun never ends, do it?

thnx again, will pass on the link to my HO... but not today, josephine. ohhhh no, not today because Cancer Care Reno changed their freakin Patient Portal... FOR THE 3rd FREAKIN TIME!!! unreal. i used the old URL and it "recognized" me, just enuff to inform me that they were now known as CARE SPACE..... like they really REALLY care!! so much so, that i now have to call the dr.'s office to get a new password and ID whatever the fuck!!!! aarrrggghh!! anyway, thnx again, pj. (did i mention pj is my step-daughter's name?)

[pjoshea13 in reply to RICH22]

Hi Rich,

My wife is being treated with Lenalidomide for a 2nd plasmacytoma. Treatment is as for multiple myeloma [MM]. My sister, who has MM, was treated with 25mg, whereas my wife was lucky enough to be put on 15mg. After 12 months, this was reduced to 10mg & she no longer has to take the Dexamethasone. What dose are you using?

The itching drove her crazy & she was told to take an antihistamine every day. Works pretty well. The itch returns occassionally, but doesn't linger.

-Patrick