ISRIB - PTEN & MYC: New study below [... - Advanced Prostate...

Advanced Prostate Cancer

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ISRIB - PTEN & MYC

pjoshea13 profile image
5 Replies

New study below [1].

Foreign terms & acronyms are a massive turnoff for some, but the idea behind the new study is quite elegant & possibly very important.

PTEN.

PTEN is a tumor suppressor gene & is often silenced in PCa.

MYC.

MYC is a regulator gene that is sometimes over-expressed in PCa. As such, it upregulates the expression of genes involved in proliferation.

PTEN loss & MYC gain.

This combination is bad news.

In theory, one would expect to see very high rates of protein synthesis in such an aggressive combination. It turns out that there is less. The reason is that uncontrolled protein synthesis would create an unacceptable level of toxicity in the cells, so the cancer triggers the ‘integrated stress response’, which inhibits a key player in protein synthesis: eIF2.

University of California, San Francisco, had already created a drug that could remove the block on eIF2: ISRIB. A decrease in eIF2 & protein synthesis is associated with memory loss. "In 2013, researchers revealed that a small drug-like molecule, called ISRIB, could prevent this decline in protein production following eIF2" inhibition. "when ISRIB was administered to mice and rats, it enhanced their long-term memories." [2]

"Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure." [1]

ISRIB will only work in PCa that has applied the brake to eIF2. This happens in cancer cells where out of control protein synthesis might lead to cell death. Restoring eIF2 levels did indeed cause the PTEN-negative/MYC-positive cells to die in this study.

-Patrick

[1] stm.sciencemag.org/content/...

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

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pjoshea13
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Sriyantra profile image
Sriyantra

Yes, this looks amazing.

VisualDeadlock profile image
VisualDeadlock

Hahaha, was logging in to post about these articles too.

TheTopBanana profile image
TheTopBanana

What happened with this?

pjoshea13 profile image
pjoshea13 in reply to TheTopBanana

Good question.

Here is the only PCa paper on PubMed (2018) - full text:

ncbi.nlm.nih.gov/pmc/articl...

More recently (not PCa):

forbes.com/sites/rebeccacof...

elifesciences.org/articles/...

-Patrick

Hope59 profile image
Hope59 in reply to pjoshea13

Kronos Bio is going to be starting a trial in first quarter of 2021 with a CDK9 Inhibitor Study in MYC-Amplified Solid Tumors.

kronosbio.com/pipeline/

precisiononcologynews.com/r...

This article requires a login, but I copied and pasted article here:

Kronos Bio to Start Phase I/II CDK9 Inhibitor Study in MYC-Amplified Solid Tumors

Dec 07, 2020 | staff reporter

NEW YORK – The US Food and Drug Administration has accepted Kronos Bio's investigational new drug application for its CDK9 inhibitor KB-0742, allowing the firm to begin clinical trials in MYC-amplified advanced solid tumors in the first quarter of 2021.

The Phase I/II study will involve a dose escalation and expansion stage. In the dose escalation stage, researchers will evaluate the safety, pharmacokinetic, and pharmacodynamic profile of KB-0742, and settle on an active and safe dose for further evaluation. In the second stage, the KB-0742 dose established in the earlier stage will be given to patients with MYC-amplified solid tumors and other rare tumors, including sarcomas and chordomas, relying on MYC overproduction for proliferation.

MYC is amplified in 30 percent of solid tumors. San Mateo, California-based Kronos said in a statement that it expects to report initial data from the dose escalation stage of the Phase I/II trial sometime next year.

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