Treatment Resistance. Enzalutamide & Exenatide (synthetic exendin-4).

[pjoshea13]

New cell study below [1].

Treatment resistance begins on day 1 of treatment. Cells under attack have a variety of survival strategies to fall back on. Activation of the the PI3K/Akt/mTOR pathway is fairly common [2].

I have long wondered why PCa drugs don't come paired with drugs to inhibit resistance. After all, if one could extend the life of a drug by a mere year, that would translate into a big bonus boost for BigPharma fat cats.

{My primary interest in phytochemical supplements is due to the possibility of inhibiting cell survival pathways.}

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From the study:

"We previously found that a GLP-1 {Glucagon-like peptide 1} analog, exendin-4 (Ex-4), inhibited the growth of prostate cancer cells through suppressing the PI3K/Akt/mTOR pathway, which is activated in response to enzalutamide treatment and reported to be closely related to resistance to enzalutamide."

"Our study demonstrated that exendin-4 alleviated resistance to enzalutamide, and suggested that exendin-4 combined with enzalutamide may be a more efficacious treatment for patients with advanced prostate cancer."

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"Exenatide (synthetic exendin-4), glucagon-like peptide-1 (GLP-1), and GLP-1 analogues have actions with the potential to significantly improve glycemic control in patients with diabetes." [3]

"Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. ... It is a less preferred treatment option after metformin and sulfonylureas." [4]

Byetta might be a nice fit for men on Enzalutamide. IMO

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/319...

Prostate. 2020 Jan 22. doi: 10.1002/pros.23951. [Epub ahead of print]

Exendin-4 enhances the sensitivity of prostate cancer to enzalutamide by targeting Akt activation.

Wenjing H1, Shao Y2, Yu Y2, Huang W2, Feng G2, Li J2.

Author information

Abstract

BACKGROUND:

Glucagon-like peptide 1 (GLP-1) and its analogs are first-line choices for the treatment of type 2 diabetes mellitus. Recent studies have shown that they exhibit antitumor properties in some tumors. We previously found that a GLP-1 analog, exendin-4 (Ex-4), inhibited the growth of prostate cancer cells through suppressing the PI3K/Akt/mTOR pathway, which is activated in response to enzalutamide treatment and reported to be closely related to resistance to enzalutamide. So we speculated that exendin-4 may enhance the sensitivity of prostate cancer to enzalutamide through inhibiting Akt activation.

METHODS:

LNCap and CWR22RV1 cell lines, as well as mice bearing xenografts formed from the two cells, were used.

RESULTS:

Exendin-4 in combination with enzalutamide dramatically suppressed tumor growth of prostate cancer cells compared to enzalutamide alone; exendin-4 is capable of antagonizing enzalutamide-induced invasion and migration of both prostate cancer cells (P < .05). Furthermore, the combination treatment significantly reduced Akt and mTOR levels that were triggered by enzalutamide administration, caused a further decrease in nuclear AR localization compared with the enzalutamide as a monotherapy (P < .5), though exendin-4 treatment alone showed no effect on nuclear AR.

CONCLUSION:

Our study demonstrated that exendin-4 alleviated resistance to enzalutamide, and suggested that exendin-4 combined with enzalutamide may be a more efficacious treatment for patients with advanced prostate cancer.

© 2020 Wiley Periodicals, Inc.

KEYWORDS:

enzalutamide; exendin-4; prostate cancer; sensitivity

PMID: 31967357 DOI: 10.1002/pros.23951

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[2] en.wikipedia.org/wiki/PI3K/...

[3] ncbi.nlm.nih.gov/pubmed/147...

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

[snoraste]

Patrick- wouldn’t Metformin do the same?

[JLS1 in reply to snoraste]

Also berberine?

[pjoshea13 in reply to snoraste]

I don't think it inhibits PI3K/Akt/mTOR.

-Patrick

[Escudilla]

I've got some homework to do! Thanks pjsohea13!

[JLS1]

Thank you so much for sharing this! -might help my husband who now needs a Hail Mary!!

Our MO felt because Zytiga stopped working that it's not even worth trying Xtandi. We had a second opinion yesterday, and that MO said even if the odds are low, that's still better than nothing at all. He said it's worth at least trying it. I wonder if adding the Exenatide with Xtandi might improve the odds it will work. However, it seems both MO's will only do SOC treatments (!!! ), so I don't know if they'll be willing to try adding the Exenatide.

Why is it SO hard to find a good MO who will go outside the SOC box?!! Is this due to liability concerns....hospital protocol????

As of 3 days ago, my husband, who has mets to bones, everywhere, is now down to the following 'treatment', while we pray his bone marrow recovers: 1mg dexamethasone + Lupron shots every 3 months + Xgeva shots monthly

We added 1 Benadryl at night to help sleep, and one 10 mg loratadine in the a.m., just because antihistamines may help slow the cancer. Figured it's safe. Pharmacist said it's ok to be taking both antihistamines this way, and that the loratadine really only lasts 12 hours.

After having great results from Zytiga + Lynparza for about 1-1/2 years (life was almost normal!), it apparently stopped working , so our MO switched from prednisone to dexamethasone to try to get a bit more from Zytiga, and stopped the Lynparza a in order to start Xofigo. The first 2 Xofigo injections were working, the 3rd was questionable, then the 4th caused bone marrow failure, which is where we are now, with our MO throwing in the towel, saying there's nothing more he can do!!! The last Xofigo was given Dec 5th, 7 weeks ago yesterday. (I know the window for bone marrow recovery is 6 - 8 weeks) He had 3 transfusions. The positive effect from the first 2 transfusions didn't last very long per weekly blood tests. However, the day of the 3rd transfusion (right before the transfusion), last Tuesday, showed numbers stabilizing, and RBC and WBC even upticked a bit - YAY! Hopefully this is sign his bone marrow can recover well enough to try other treatments. If he can recover, one possibility is - He's on a list for the AC225 via Weill Cornell. Interestingly, they now are sending patients to Tulane in New Orleans to get the treatment.