Zytiga, Akt & PTEN.

[pjoshea13]

New international study below [1] - author is Johan de Bono, Royal Marsden.

But first some background on the PI3K-AKT-mTOR signaling pathway [2]:

"The PI3K-AKT-mTOR signaling pathway is an ancient signal transduction pathway, conserved from worms to humans, that has evolved into an essential regulator of catabolic and anabolic processes in a cell. It provides a critical nexus that connects nutrient and growth factor sensing with a variety of vital cellular processes, including protein synthesis, proliferation, survival, metabolism and differentiation."

"Given the critical role of the PI3K-AKT-mTOR pathway in normal cell physiology, it is not surprising that the pathway is deregulated in a vast array of cancers. In fact, genetic alterations have been identified in nearly every member of the pathway. In PCa, the PI3K-AKT-mTOR signaling pathway is deregulated in 42% of localized disease and 100% of advanced-stage disease, which implies that alterations in this pathway may be a pre-requisite for the development of CRPC."

...

"Ipatasertib (RG7440) is an experimental cancer drug in development by Roche. It is a small molecule inhibitor of Akt." [3]

...

In the new study, "Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1000 mg twice daily orally."

radiographic progression-free survival "was prolonged in the ipatasertib cohort vs placebo, with similar trends in overall survival and time-to-PSA progression."

"A larger {radiographic progression-free survival} prolongation for the combination was demonstrated in PTEN-loss tumors vs those without."

"In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors."

...

PI3K-AKT-mTOR & supplements:

"Our study demonstrates that {Ursolic acid} not only inhibits cell growth but also induces apoptosis through modulation of the PI3K/Akt/mTOR pathway in human prostate cancer cells. We suggest that {Ursolic acid} may be a new chemotherapeutic candidate against prostate cancer." [4]

Source: holy basil, e.g. [5].

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/300...

Clin Cancer Res. 2018 Jul 23. pii: clincanres.0981.2018. doi: 10.1158/1078-0432.CCR-18-0981. [Epub ahead of print]

Randomized Phase II Study of Akt Blockade With or Without Ipatasertib in Abiraterone-Treated Patients With Metastatic Prostate Cancer With and Without PTEN Loss.

de Bono JS1, De Giorgi U2, Nava Rodrigues D3, Massard C4, Bracarda S5, Font A6, Arranz Arija JA7, Shih KC8, Radavoi GD9, Xu N10, Chan WY11, Ma H10, Gendreau S12, Riisnaes R13, Patel P14, Maslyar DJ10, Jinga V15.

Author information

1

The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust [e-mail].

2

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) - IRCCS.

3

The Institute of Cancer Research.

4

Medical Oncology, Gustave Roussy.

5

Ospedale San Donato, Azienda.

6

Oncology Unit, Catalan Institute of Oncology, Hospital Germans Trias i Pujol.

7

Hospital General Universitario Gregorio Marañón.

8

Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology,PLLC.

9

Carol Davila University of Medicine and Pharmacy, Bucharest.

10

Genentech, Inc., South San Francisco.

11

Genentech, Inc.

12

Oncology Biomarker Development, Genentech Inc.

13

Division of Clinical Studies, The Institute of Cancer Research.

14

Early Clinical Development, Genentech, Inc.

15

Th. Burghele Hospital, Carol Davila University of Medicine and Pharmacy.

Abstract

PURPOSE:

PI3K-Akt-mTOR and AR signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase 1b/2 study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC.

EXPERIMENTAL DESIGN:

Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1000 mg twice daily orally. Co-primary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors.

RESULTS:

rPFS was prolonged in the ipatasertib cohort vs placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors vs those without. The combination was well tolerated, with no treatment-related deaths.

CONCLUSION:

In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.

Copyright ©2018, American Association for Cancer Research.

PMID: 30037818 DOI: 10.1158/1078-0432.CCR-18-0981

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

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

[4] ncbi.nlm.nih.gov/pubmed/265...

[5] swansonvitamins.com/swanson...

[Dan59]

Thank You for posting Patrick. Interesting to read that ipatasertib(new drug in trial at RM) had better response in those of us lacking PTEN.

Also intersting to read about the effects of Ursolic acid, Is that not the same Ursodiol that Doc Myers used to prescibe us as liver protectant?

Dan

[pjoshea13 in reply to Dan59]

Dan,

It may interest you that:

"The naturally occurring compound ursolic acid and the licensed drug ursodeoxycholic acid {ursodiol} are chemically closely related to ..."

"We ... propose both ursolic acid as a naturally occurring compound, and ursodeoxycholic acid as an already licensed drug as promising compounds for future neuroprotective trials in Parkinson's disease."

ncbi.nlm.nih.gov/pubmed/240...

-Patrick

[Dan59 in reply to pjoshea13]

That is excellent!!! Old Snuffy had something there, after I had liver prob with casodex 150 he had me on Urso and I never had liver numbers above lower limit of normal on any other therapy, never did casodex again. Who knew it was chemotheraputic as well ? I have not done in in over 6 yrs, but I think I have some in my drawer.

[tallguy2]

Thank you for posting these results. I am likely to start abiraterone this fall after completing chemo; I will bring this to the attention of my MO.

[leswell]

Hello, Patrick. I replied earlier in the wrong location about your hernia as follows:

“This is one more development you did not need! Your decision is more complicated than ours, but we hope for successful surgery in spite of your previous RPD. Wishing you wisdom and the best surgeon. And now back to your post on ipatasertib, Zytiga, AKT, PTEN, Ursolic acid, and HOLY BASIL. Interesting”

And now tonight, Patrick. Les and I are wondering what is being done about your hernia. In view of your long term multi-faceted treatment and survival, we are concerned.

In my brief research about this your more recent post, I read the following and would appreciate your input. Do you know of anyone not in trial and within a couple months of beginning Zytiga + prednisone adding ipatasertib or, if already on Zytiga, is it too late to start?

From OncLive which indicates that in the international phase III IPATential150 trial (NCT03072238, participants must not have been previously treated for mCRPC. Tumor samples must be tested for phosphates and PTEN loss on an immunohistochemistry assay (Sep 07, 2017). Btw, how are they acquiring a tumor sample, and isn’t there a danger of cancer spread from any needle biopsy?

Also, see the following from OncLive related to taking Zytiga or Xtandi in the first place:

CTC AR-V7 Assay Shows Promise as Treatment Guide in mCRPC

Jason Harris

Published: Tuesday, Jul 17, 2018

Why aren’t oncologists and prostate cancer specialists insisting on an AR-V7 Assay as a matter of course?

Love and best wishes to you and Nal whenever you lunch. Leswell and spouse

[leswell]

P.S. We listened to the two following young performers at the end of the day:

youtu.be/PM0HqmptYlY(Not working as expected?)

youtu.be/2bFo65szAP0(Not working as expected?)

Go well.