Cancer pill fights disease and gives lifelong protection??

[novatimo]

Does anyone have any additional info on this 2014 development?

Cancer pill fights disease and gives lifelong protection

telegraph.co.uk/news/scienc...

[Neal-Snyder]

I've never heard of it but it sounds pretty exciting. Presumably, it's working its way through an expedited clinical trail process, not necessarily including PC, & wouldn't be available to anyone yet who isn't in a clinical trial. If you don't get any feedback from someone who knows the current research status, including whether it's being studied for PC, you might want to do searches for more info. Thanks for the news!

[aupauledwards in reply to Neal-Snyder]

Yet another cure for cancer in mice!

[pjoshea13]

I tend to skip articles that don't specifically mention PCa, unless a familiar technical term catches my eye. Delta-inhibitors & p100delta meant nothing to me, & there are no PCa papers that I could find that used both of those terms.

But PI3K (not mentioned in the story) I do know about. PI3K often appears in PCa papers in the context of the PI3K/Akt/mTOR signaling pathway (which cropped up in my recent mTOR post). A common event in PCa is loss of PTEN, which leads to activation of the PI3K/Akt/mTOR pathway. Suffice to say, PI3K is an attractive target (although inhibition can lead to upregulation of the androgen receptor.)

New to me is that PI3K has four variations - delta being the fourth. It appears that the target, unmentioned in the story, is PI3Kδ.

There are plenty of PI3Kδ hits on PubMed, but only 4 that relate to PCa. The latest (this month) [1]:

"... showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-deficient PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing."

Essentially, the researchers have discovered a promising PI3Kδ inhibitor. (Apologies for not translating the quoted passage. What should be clear is that the lab is looking for PI3Kβ/δ inhibitors that are effective against PCa.) But no mention of the effect on immune response.

In an earlier study [2], the drug AZD8186 was used against PCa cells:

"We have developed a small-molecule inhibitor of PI3Kβ and PI3Kδ (AZD8186) and assessed its antitumor activity across a panel of cell lines."

"In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate ... tumors."

"PI3Kα and β are expressed in most normal tissues, whereas PI3Kδ is thought to be restricted to the immune system." (No other reference to 'immune'.)

The first human trial of AZD8186 [3] is currently recruiting:

"This is a phase I, open-label, multicentre study of AZD8186 administered orally in patients with advanced castrate-resistant prostate cancer (CRPC), squamous non-small cell lung cancer (sqNSCLC), triple negative breast cancer (TNBC) and known PTEN-deficient/mutated or PIK3CB mutated/amplified advanced solid malignancies as monotherapy and in combination with abiraterone acetate or AZD2014."

Other PI3Kδ inhibitor drugs:

[A] Idelalisib

en.wikipedia.org/wiki/Idela...

"In July 2014, the FDA and EMA granted idelalisib approval to treat different types of leukemia.[7][13] The FDA is also granted approval for idelalisib to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma."

[B] CDZ173

nibr.com/stories/nerd-blog/...

"“We had biomarkers indicating preliminarily that it was effective in inhibiting the PI3 kinase-delta pathway,” Christ says.

The scientists had not expected that CDZ173 would help with immunodeficiency, a quite different condition. But when the PI3 kinase-delta papers came out, “we immediately realized that our investigational drug might work in these patients,” he says. “We already had sufficient clinical data to allow us to do clinical studies.”

[C] INCB050465

[D] INCB040093

[E] HMPL-689

[F] AMG 319

Each is in a clinical trial.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/269...

[2] mct.aacrjournals.org/conten...

[3] clinicaltrials.gov/ct2/show...

[BigRich in reply to pjoshea13]

Patrick, I like it that you list the reference sources. I find your posts informative.

[Attitude67]

Novatimo, FYI:

The first Delta Inhibitors are here.

Clinical Trails for P-13 have started in San Diego, Ca. The first-in-human study of MEI Pharma's investigational drug candidate, ME-401, a next generation oral PI3K delta inhibitor. The data, were presented at the American Association for Cancer Research (AACR) Annual Meeting in New Orleans, this April. It suggests that ME-401 has an excellent pharmacokinetic (PK) and pharmacodynamic (PD) profile and the potential for an improved therapeutic window compared to other PI3K delta inhibitor.

Be advised that the first approved delta type drug idelalisib (marketed as Zydelig®), was fast tracked for blood bourne cancers and is presently in use at most university based treatment centers.

[dave2]

"p100delta" appears to be a typo in the article. Later in the same article "p110 delta" (an isoform of PI3K) is mentioned. As Patrick has pointed out, lots of research is underway regarding inhibition of PI3K signaling, along with Akt and mTOR. Unfortunately, the data so far indicate that although multiple potential therapeutic agents have been developed to inhibit elements of this pathway, it is very complex and characterized by many mutations in cancer patients. Early therapeutic resistance to PI3K inhibitors appears to be one of the challenges. Despite this, the investigation is still in its early phase and many are optimistic that PI3K inhibitors (possibly used in combination with other treatments) will become a useful therapeutic tool for prostate and other cancers.

Best article I found on this topic: am.asco.org/exploring-pathway-despite-lukewarm-clinical-benefit-pi3k-inhibitors-optimism-remains-regarding

Dave