ASCO Genitourinary Cancers Symposium (Hypoxia related mRNA biomarker to predict biochemical failure and metastasis)

[pjoshea13]

This is very much of interest to me.

PCa tumors run into trouble when they outgrow their blood supplies. Unfortunately, the cells respond to a shortage of oxygen (hypoxia) in such a way that current treatments become largely ineffective.

The internet is full of bogus info. about cancer "hating oxygen". In fact, PCa cells in a hypoxic state are very hard to kill. They are stressed, but do just fine.

And one of their responses is the building of new blood vessels (angiogenesis). If we could prevent angiogenesis we could limit tumor size.

The paradox is that appeasement - continuation of the oxygen supply - is currently the best strategy IMO.

For men on ADT, or even with "normal" age-related testosterone, there is a decline in red blood cells [RBCs]. The hemoglobin in RBCs carry oxygen from lungs to cells. As a population, we are limited in how much oxygen we can get into the blood.

What we can do is dilate the blood vessels to improve supply to the tumor. This was tried in a 2009 Canadian study [1]. "The calculated PSADT of the treatment group before initiating GTN was 13.3 months ... In an intention-to-treat analysis, the end-of-study PSADT for the treatment group was significantly different at 31.8 months".

They used low-dose glyceryl trinitrate patches to release nitrix oxide [NO] into the blood. NO dilates the vessels.

I currently use a 0.1 mg/hr nitroglycerin patch for that purpose.

"The prolongation of the PSADT and the safety of the drug, coupled with the corresponding preclinical in vitro and in vivo data documenting the ability of nitric oxide to attenuate hypoxia-induced progression of prostate cancer, warrant further testing in a placebo-controlled study."

Excuse the lengthy preamble, but the new study is merely concerned with identifying men with the hypoxic response:

"Hypoxia related mRNA biomarker to predict biochemical failure and metastasis for prostate cancer." [2]

"Hypoxia is an important regulatory factor in tumorigenesis and is associated with a poor prognosis."

"Patients stratified as high hypoxia were associated with significantly poorer 5-year biochemical recurrence free survival in patients undergoing prostatectomy alone, prostatectomy plus adjuvant radiotherapy and definitive radiotherapy alone."

"In another cohort of prostatectomy and salvage radiotherapy treated patients, the mRNA signature predicts metastasis free survival ..."

"We derived a de novo mRNA signature based on hypoxia- regulated genes. The biomarker consistently predicts biochemical failure and metastasis for prostate cancer patients with localized disease."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/194...

[2] 5 Rapid-Fire Abstract Session, Thu, 5:15 PM-6:15 PM and Poster Session

(Board #A9), Thu, 11:30 AM-1:00 PM and 5:15 PM-6:15 PM

Hypoxia related mRNA biomarker to predict biochemical failure and metastasis for prostate cancer.

Ananya Choudhury, Lingjian Yang, Darren Roberts, Mandeep Takhar, Bhandari Vinayak, Becky Bibby, Wei-chen Cheng, Syed Haider, Niluja Thiruthaneeswaran, Peter Hoskin, Darragh McArt, Suneil Jain, Francesca Meteora Buffa, Nicholas Erho, Robert G. Bristow, Paul Christopher Boutros, Elai Davicioni, Catharine West; Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom; University of Manchester, Manchester, United Kingdom; GenomeDx Biosciences Inc., Vancouver, BC, Canada; University of Toronto, Toronto, ON, Canada; University of Manchester, Manchester, GB; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; University of Oxford, Oxford, United Kingdom; Mount Vernon Cancer Centre, London, United Kingdom; Queen’s University Belfast Center for Cancer Research and Cell Biology, Belfast, United Kingdom; Queen’s University Belfast, Belfast, United Kingdom; Manchester Cancer Research Centre, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada; GenomeDx Biosciences Inc., San Diego, CA

Background: Hypoxia is an important regulatory factor in tumorigenesis and is associated with a poor prognosis. Patients with high risk locally advanced disease account for 13-21% of prostate cancer cases and the ten year cancer specific survival rate for these patients is 62%. Patients with hypoxic tumours could benefit from hypoxia modifying therapeutics in addition to radiotherapy. Clinical companion biomarkers are needed to stratify patients who would benefit from hypoxia modifying therapy in addition to radiotherapy.

Methods: RNA-seq analysis was performed on prostate cell lines (PNT2-C2, PC-3, LNCaP and DU145) exposed to 1% hypoxia for 24 hrs. A prostate cancer hypoxia gene signature was derived in silico using publicly available prostate gene expression data sets and the RNA-seq data. The biomarker was then independently validated in multiple cohorts of prostate cancer patients with localized diseases receiving prostatectomy alone, prostatectomy plus adjuvant radiotherapy, prostatectomy plus salvage radiotherapy, or definitive radiotherapy alone.

Results: In vitro the hypoxia inducible expression of the hypoxia gene signature was tested at 1% and 0.1% oxygen of which 21 of the 28 genes were regulated by hypoxia. Patients stratified as high hypoxia were associated with significantly poorer 5-year biochemical recurrence free survival in patients undergoing prostatectomy alone, prostatectomy plus adjuvant radiotherapy and definitive radiotherapy alone. In multivariable analysis, the biomarker retained significance after correcting for confounding factors including Gleason group, PSA, a molecular classifier, etc. In another cohort of prostatectomy and salvage radiotherapy treated patients, the mRNA signature predicts metastasis free survival in both univariable and multivariable analyses.

Conclusions: We derived a de novo mRNA signature based on hypoxia- regulated genes. The biomarker consistently predicts biochemical failure and metastasis for prostate cancer patients with localized disease.