RRx-001?: New paper below [... - Advanced Prostate...

Advanced Prostate Cancer
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RRx-001?

pjoshea13
pjoshea13

New paper below [1].

"Complete metabolic response of metastatic castration-resistant neuroendocrine carcinoma of the prostate after treatment with RRx-001 and reintroduced platinum doublets."

The authors had an earlier paper with the same title, but no Abstract [2].

& that's all there is as far as PCa goes.

Why am I intrigued?

In 2014 there was a similar paper [3] (2 colorectal cases), but with a lot more info on RRx-001:

"RRx-001 is a novel, hypomethylating and free-radical-inducing anticancer agent that activates nitrite reduction to NO under hypoxia and has an impact on epigenetic pathways. The repression of DNA methyltransferase 1 by RRx-001 may lead to demethylation and reexpression of silenced tumor suppressor genes, leading to resensitization."

***

"RRx-001 is a novel, small-molecule, hypomethylating agent with pro-oxidant-induced anticancer activity including the inactivation of DNA methyltransferase 1 (DNMT1) and a favorable toxicity profile compared with standard cytotoxic and targeted agents. RRx-001, sourced from the aerospace industry, alters the structure and function of hemoglobin, leading to the intensive production of reactive oxygen and nitrogen species within a small subset of red blood cells. The changes in structure and nitrite reductase function of hemoglobin result in increases in the oxidative state of red blood cells through NO production and free radical release that increases tumor levels of reactive oxygen and nitrogen species and changes vascular flow, particularly in the hypoxic milieu of the tumor, leading to epigenetic effects that include the oxidation and inactivation of DNMT1. DNMT1 in cancer is associated with hypermethylation and thereby silencing of CpG islands of tumor suppressor genes such as p53. The viability of tumor cells is highly dependent on the tumor microenvironment for oxygen derived from blood, but also on the supporting cells within this environment. RRx-001 disrupts the blood flow to tumors, presumably through NO generation and thereby reactive oxygen and nitrogen species levels, enhancing hypoxic cell death. These effects could also alter critical cell-to-cell signaling within the tumor stroma that can potentiate cancer cell death while minimizing normal tissue toxicity. The changes in tumor blood flow and intercellular signaling patterns caused by RRx-001 put tumor cells under fundamentally different environmental stress than genotoxic chemotherapeutic agents. Consequently, cells adapted to survival after exposure to genotoxic agents may not be well adapted to survival under conditions inducted by altering NO levels within a tumor. During the course of conducting a phase-1 study of patients with various cancers treated with RRx-001, we observed several patients who had enrolled with rapidly progressive disease in whom tumor growth was arrested for periods of 6–9 months while on study. A state of persistent, stable disease is unusual among such patients. The eventual progression of disease in these patients suggested that these tumors adapted to the selective anticancer pressure applied by RRx-001. However, since many months are required for adaption to RRx-001, changes in the gene expression profiles of these tumors are to be expected. Resensitization to genotoxic chemotherapeutic agents indicates that fundamental changes in chemoresistance patterns could have occurred."

"The safety of RRx-001 administered once/week i.v. has been demonstrated in a phase-1 dose escalation study where RRx-001 was generally well tolerated, without clinically significant drug-related laboratory abnormalities or systemic toxicity. Moreover, subjects with a broad range of cancer types, including the pancreas, lung, colon, head and neck, brain and ovaries, experienced clinical monotherapeutic benefit as measured by an improvement in tumor-related symptoms in conjunction with shrinkage or stabilization of their tumor using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1."

***

Many of the changes that occur in prostatic cells on the way to becoming PCa are epigenetic, i.e. the affected genes are not mutated but silenced, often via methylation. (Beware of methyl particularly in supplements such as folic acid & SAMe.) Treatment resistance may also involve epigenetic changes.

It's refreshing to read about a potentially useful drug that (a) does NOT target the androgen receptor [AR] axis, & (b) finally recognizes that hypermethylation is an attractive target. PCa cells suck up methyl delivered by SAM & are known to be hypermethylated.

The penultimate paragraph brightened a dreary rainy day in Asheville:

"This clinically significant tumor resensitization to previously inactive chemotherapy suggests that the tumor adaptation to the novel hypoxia-activated, prooxidant hypomethylating agent RRx-001 oxidatively inactivated critical cysteine residues on enzymes such as DNMT1. This redox modification resulted in epigenetic changes, leading to a window of opportunity for the reintroduction of standard cytotoxic therapies such as FOLFOX or FOLFIRI to which resistance had previously developed. This concept challenges the entrenched clinical dogma of ‘once refractory always refractory’."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/305...

Clin Case Rep. 2018 Nov 5;6(12):2478-2481. doi: 10.1002/ccr3.1880. eCollection 2018 Dec.

Complete metabolic response of metastatic castration-resistant neuroendocrine carcinoma of the prostate after treatment with RRx-001 and reintroduced platinum doublets.

Ojemuyiwa M1, Zeman K1, Spira A2, Oronsky B3, Ray C4, Trepel JB5, Lee MJ5, Onyiuke I6, Brzezniak C1.

Author information

1

Walter Reed National Military Medical Center Bethesda Maryland.

2

Virginia Cancer Specialists (VCS) Fairfax Virginia.

3

EpicentRx San Diego California.

4

St. Francis Hospital & Medical Center Hartford Connecticut.

5

Developmental Therapeutics Branch National Cancer Institute, NIH Bethesda Maryland.

6

VA Connecticut Health Care System West Haven Connecticut.

Abstract

Presented herein is the case of a heavily pretreated patient with high-grade neuroendocrine prostate cancer that achieved a complete metabolic response on platinum-based chemotherapy after treatment with the dual CD-47 and SIRP-α inhibitor, RRx-001, in a Phase II clinical trial.

KEYWORDS:

RRx‐001; macrophage repolarization; neuroendocrine cancer; platinum doublets; priming; prostate cancer

PMID: 30564353 PMCID: PMC6293266 DOI: 10.1002/ccr3.1880

***

[2] ncbi.nlm.nih.gov/pubmed/289...

[3] ncbi.nlm.nih.gov/pmc/articl...

21 Replies
oldestnewest

It is intriguing....when it gets to neuroendocrine, that's tough and RRx-001 halted tumor progression for 6-9 months...the article did not mention if any clinical trial participants actually had chemo afterwards but mentioned, "a window of opportunity" ,where chemo could work. That's the missing info IMHO....Did anyone get chemo? Did they push the beast backwards further....Good news.....just wish the "rest of the story" was known....Great find, Patrick....Thank you....

Very top notch interesting--would like to know the molecule RRx-001--If I can see the molecular structure, I can maybe determine the reactive sites. This info would be cool for me to have. But I am sure, this is the possible patent protection, the developers will need. That is why they assign numbers.

Nalakrats

Is this it--not too hard to synthesize--if I had my old lab back.

Nalakrats

That's the image I found...

Interesting, its base is not from nature--might be a completely fabricated molecule.

Nalakrats

The drugs they are creating are mind boggling.....when I read about cyclic peptoids and that they "stapled"--ie: attached an additional component to "stiffen" it up so it could bind with pCa....which blocked reproduction and made it capable of reducing the growth by 95% in vitro----incredible....hope it can get into trials...anything to slow it down, stop it, kick its' tail....great...

podsart
podsart
in reply to Nalakrats

This quite exciting , hyper methylation of PTEN and P53 via epigenetic changes, caused , among other reasons ,by long periods hi stress - many years- allowing persistent cortisol, epinephrine etc to epigenetically cause hyper methylation - seems to open the gates to Pca .

Knowing the structure, are any of your supplements , perhaps in tandem, similar to this fabricated molecule?

Nalakrats
Nalakrats
in reply to podsart

Not even close--this appears to be a created lab molecule from what I can see--hells bells, i do not know all that exists in nature, but just looking at it with the bromine attachment is not something I would think is in nature. Looks like they were trying to create a scenario, for hypermethylation. It has been 15-18 years that I walked into a Lab and said hello to my research team.

Nalakrats

pjoshea13
pjoshea13
in reply to Nalakrats

From my post:

"RRx-001, sourced from the aerospace industry" !!!

-Patrick

Nalakrats
Nalakrats
in reply to pjoshea13

What were they doing making a new fuel---when I see all those NO Groups I think of explosives.

Nalakrats

I wonder how far away from ready availability this is.

NPfisherman
NPfisherman
in reply to cesanon

Phase 3

cesanon
cesanon
in reply to NPfisherman

How many years do you think?

NPfisherman
NPfisherman
in reply to cesanon

Ya never know...they may find that when they test it against something else that it is so superior that it gets approved in less than 3 years...if it is clearly saving lives, the FDA has a fast track process....if you saw some other posts, the primary cancer is not prostate....I like the post below this....wish I could have posted the image...

About Entering Phase 3 RRx-001

A new class of anti-cancer therapy with the potential to convert “treatment-resistant” tumors into “treatment sensitive” tumors

First-generation therapies, which target “checkpoint inhibitors”, have revolutionized the treatment of cancer, but only a small set of patients derives benefit. One of the reasons that not all patients respond to treatment is the presence of myeloid-derived suppressor cells in the tumor microenvironment.

Multimechanistic RRx-001 is a first-in-class small molecule immunotherapeutic that targets the CD47 – SIRPα axis and repolarizes tumor associated macrophages (TAMs) and other immunosuppressive cells in the tumor microenvironment to an immunostimulatory phenotype.

RRx-001 can be used as monotherapy or in combination with chemotherapy, radiation therapy or immunotherapy as an anti-cancer therapy, which also protects normal tissues.

RRx-001 was recently granted orphan drug designation for SCLC and neuroendocrine cancer in the US by the FDA and for SCLC in Europe by the EMA.

Again, Patrick....hats off....I had never heard of this till you posted...great potential for many here....guess I need to look at more than prostate cancer trials...

cesanon
cesanon
in reply to NPfisherman

Yes, thank you Patrick

Thanks for this new hope, Patrick. Merry Christmas! Jan and Les

Dazed and Dazzled as usual.......

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 12/21/2018 5:35 PM EST

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