Extreme Chronic Undervalue, page-195

There is no where to go - nobody to ask about this stuff.

However, it is basic understanding of plain english for somebody to appreciate the significance of stories like this.........that are flooding through every week.

These old PI3k and AKT inhibitor drugs - make patients sick and have documented modest clinical activity in single  isoforms & don't work in the brain.  eg  -PIQRAY inhibits the α isoform of PI3K, which  is 50 times more potently than other PI3K isoforms (β, γ, δ..

50 times in alpha - sounds good, but is that going to stop the loss of PTEN - not according to Dana Farber Jean Zhao, in GBM at least. (my recent posts, or research yourself)

I acknowledge though - this is deep research and near impossible for most punters to understand. It is important though - at least for me and I think very keen followers to consider the possibility of their drug paxalisib - being that general purpose cancer PI3K drug inhibitor and in fact do the job here, in prostrate and many other cancers.

Hopefully the story itself, explains to you about the loss of PTEN caused by deregulated PI3K pathway....and the benefits of "repairing" the pathway with these PIK inhibitors.

To really wake everybody up - highly creditable information, at the very bottom.... below about the hundreds and hundreds of existing clinical trials in

PI3K/AKT/mTOR Inhibitors for Prostate Cancer – Finally Hints of a Breakthrough
Published 05 January 2021

Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has been strongly linked with prostate cancer progression and metastatic potential.¹ Loss of the inhibitory phosphatase, PTEN, leading to hyperactivation of PI3K/AKT/mTOR oncogenic signaling, occurs in 40-50% of metastatic castration-resistant prostate cancer.^1,2 Not surprising is the fact that PTEN loss in patients with metastatic castration-resistant prostate cancer is associated with a worse prognosis and less benefit from androgen receptor (AR) blockade.³ Likewise, PTEN loss and subsequent Akt activation confer radiation⁴ and chemotherapy^{5, 6} resistance.

Highly relevant to therapeutic development in prostate cancer, PI3K/Akt/mTOR and AR signaling pathways regulate one another through reciprocal feedback mechanisms.^{7, 8} Since AR blockade is the hallmark of initial systemic therapy for men with advanced prostate cancer, the recognition that the PI3K/Akt/mTOR is subsequently activated, enabling prostate cancer cell survival, offers a rational therapeutic target in this situation.

Early attempts to inhibit this signaling pathway were dedicated to the inhibition of mTOR. Rapamycin offered a pharmacodynamic effect to inhibit the intended target, however, there was no significant antineoplastic activity.^{9, 10} TORC1 inhibitors, temsirolimus^{11, 12} and everolimus^{13, 14} also lacked significant efficacy. It was actually not surprising that these agents lacked efficacy, as sole inhibition of TORC1 will lead to downregulation of S6Kinase, a negative regulator of TORC2. TORC2 will then serve as positive feedback to further activate Akt.¹⁵ Hence, this theory and subsequent preclinical data supported the superior efficacy of dual TORC1 and TORC2 inhibition over TORC1 inhibition alone, and the result was prevention of prostate cancer invasion and induction of apoptosis.¹⁶ Unfortunately, early attempts at dual inhibition TORC1 and TORC2, with agents like dactolisib (BEZ2350)^{17, 18} and MLN0128¹⁹ have been met with significant toxicity and limited efficacy.

As dactolisib is also a pan-PI3K inhibitor, early attempts at PI3K inhibition in prostate cancer have also been met with limited efficacy. PX-866 also had very modest single-agent activity and an attempt to add abiraterone to reverse resistance due to reciprocal activation between AR and PI3K/Akt/mTOR signaling was not successful.²⁰ Buparlisib (BKM-120) is the most widely studied PI3K inhibitor in prostate cancer. The strategy to reverse resistance saw the addition of buparlisib to novel AR pathway inhibitors, abiraterone¹⁷, and enzalutamide,²¹ yet efficacy results were also disappointing.

Naturally, another key component of the PI3K/Akt/mTOR pathway to explore is to inhibit Akt. In the PROCAID trial, capivasertib (AZD5363), an oral pan-Akt inhibitor, was combined in a Phase I clinical trial with docetaxel and prednisolone for patients with metastatic castration-resistant prostate cancer, and a recommended Phase II dose was determined for this combination.²² Ipatasertib, an oral small molecule that binds to the ATP-binding pocket of all three isoforms of Akt, has been the most studied Akt inhibitor in prostate cancer. A randomized Phase II trial demonstrated that ipatasertib, in combination with abiraterone, led to prolonged radiographic progression-free survival (rPFS) over placebo with abiraterone.²³ The effect on rPFS was even greater in patients with PTEN-loss in their tumors compared to those with intact PTEN.

As a result, the IPATential150 randomized, Phase III trial of abiraterone with ipatasertib 400 mg PO QD vs. abiraterone with placebo was recently performed, and an oral presentation was delivered at the European Society of Medical Oncology.²⁴ The trial randomized 1,101 patients in a 1:1 fashion with co-primary endpoints of investigator-assessed rPFS by Prostate Cancer Working Group 3 criteria in the intention to treat (ITT) population and also in the PTEN-loss population.²⁵ PTEN-loss was defined by immunohistochemistry using a different method than many other clinical trials, which typically require at least 90% of tumor area with no detectable PTEN staining. In this trial, only a minimum of 50% of the specimen’s tumor area with no detectable PTEN staining by the Ventana SP218 antibody was required to be included in the PTEN-loss group. These criteria were met by 521 patients. The most striking finding from the trial was that that rPFS was improved in the ipatesertib plus abiraterone group over the placebo plus abiraterone group (median rPFS 18.5 vs. 16.5 months, respectively), with a stratified hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.61-0.98, p=0.0335, statistical significance set at α=0.05). For practical purposes, rPFS in the next generation sequencing defined PTEN-loss population was also significant with a median rPFS 19.1 vs. 14.2 months, respectively (HR 0.65; 95% CI 0.45-0.95, p=0.0206). The ITT population was not statistically significant (median rPFS 19.2 vs. 16.6 months, respectively) with a stratified HR 0.84; 95% CI 0.71-0.99, p=0.0431, statistical significance set at α=0.01). Secondary endpoints of confirmed objective response, PSA response, and time to PSA progression all favored the ipatasertib arm. At this time, overall survival data is not yet mature.

The above data is incredibly intriguing. The body of evidence is that the PI3K/Akt/mTOR signaling pathway is highly important in advanced prostate cancer. Yet we just have not had the therapeutic agents or clinical trials to be able to conclusively prove clinical benefit. The hope is that the data with ipatasertib successfully matures and that we better learn how to identify and define the PTEN-loss population. In the meantime, there are multiple ongoing clinical trials with ipatasertib and other Akt inhibitors that we have an opportunity to accrue to. The promising results above should only encourage us to have greater enthusiasm to accrue to these trials below.

Highlighted trials testing Akt inhibitors in patients with metastatic prostate cancer:

• Phase 1b trial of ipatasertib in combination with atezolizumab and docetaxel for metastatic castration-resistant prostate cancer (NCT04404140)
• IceCAP – Phase 1 trials of ipatasertib in combination with atezolizumab for metastatic castration-resistant prostate cancer with PTEN-loss (NCT03673787)
• PC-BETS – ctDNA driven precision design including an ipatasertib cohort (NCT03385655)
• Phase 1b trial of ipatasertib or apitolisib with abiraterone vs. abiraterone alone in metastatic castration-resistant prostate cancer patients previously treated with docetaxel (also includes a lower ipatasertib 200 mg PO QD dosing arm) (NCT01485861)
• CAPItello-281 – Randomized phase 3 trial of capivasertib plus abiraterone plus androgen deprivation therapy vs. placebo plus abiraterone plus androgen deprivation therapy for PTEN deficient metastatic hormone-sensitive prostate cancer (NCT04493853)
• Phase 1/2 trial of afuresertib with androgen synthesis enzyme inhibitor, LAE001 in metastatic castration-resistant prostate cancer patients who have received at least 2 novel hormonal therapy agents and docetaxel or cabazitaxel (NCT04060394)

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

----------------------------------------------------
kers /
PTEN Loss
Back to Biomarkers List

Associated Genetic Biomarkers
Overview

Gene Location [1]
10q23.31
Pathway
PI3K/AKT1/MTOR
Variant Type
Loss
Gene
PTEN
PTEN Loss is present in 1.72% of AACR GENIE cases, with prostate adenocarcinoma, conventional glioblastoma multiforme, breast invasive ductal carcinoma, colon adenocarcinoma, and glioblastoma having the greatest prevalence [4].
Top Disease Cases with PTEN Loss

Clinical Trials
View Clinical Trials for PTEN Loss
Significance of PTEN Loss in Diseases
mce-anchor
Malignant Solid Tumor-
PTEN is altered in 8.13% of malignant solid tumor patients with PTEN Loss present in 1.89% of all malignant solid tumor patients [4].
PTEN Loss is an inclusion criterion in 37 clinical trials for malignant solid tumor, of which 28 are open and 9 are closed. Of the trials that contain PTEN Loss and malignant solid tumor as inclusion criteria, 14 are phase 1 (8 open), 8 are phase 1/phase 2 (6 open), 14 are phase 2 (13 open), and 1 is phase 4 (1 open) [5].
mce-anchor
Breast Carcinoma-
PTEN is altered in 7.35% of breast carcinoma patients with PTEN Loss present in 1.61% of all breast carcinoma patients [4].
PTEN Loss is an inclusion criterion in 29 clinical trials for breast carcinoma, of which 24 are open and 5 are closed. Of the trials that contain PTEN Loss and breast carcinoma as inclusion criteria, 8 are phase 1 (5 open), 5 are phase 1/phase 2 (4 open), 13 are phase 2 (12 open), and 3 are phase 3 (3 open) [5].
mce-anchor
Prostate Carcinoma-
PTEN is altered in 17.77% of prostate carcinoma patients with PTEN Loss present in 11.6% of all prostate carcinoma patients [4].
PTEN Loss is an inclusion criterion in 14 clinical trials for prostate carcinoma, of which 8 are open and 6 are closed. Of the trials that contain PTEN Loss and prostate carcinoma as inclusion criteria, 5 are phase 1 (1 open), 2 are phase 1/phase 2 (1 open), 5 are phase 2 (4 open), and 2 are phase 3 (2 open) [5].
mce-anchor
Ovarian Carcinoma-
PTEN is altered in 4.06% of ovarian carcinoma patients with PTEN Loss present in 1.22% of all ovarian carcinoma patients [4].
PTEN Loss is an inclusion criterion in 12 clinical trials for ovarian carcinoma, of which 7 are open and 5 are closed. Of the trials that contain PTEN Loss and ovarian carcinoma as inclusion criteria, 3 are phase 1 (1 open), 3 are phase 1/phase 2 (2 open), 5 are phase 2 (4 open), and 1 is phase 3 (0 open) [5].
mce-anchor
Non-Small Cell Lung Carcinoma-
PTEN is altered in 3.33% of non-small cell lung carcinoma patients with PTEN Loss present in 0.51% of all non-small cell lung carcinoma patients [4].
PTEN Loss is an inclusion criterion in 11 clinical trials for non-small cell lung carcinoma, of which 5 are open and 6 are closed. Of the trials that contain PTEN Loss and non-small cell lung carcinoma as inclusion criteria, 2 are phase 1 (0 open), 6 are phase 1/phase 2 (3 open), and 3 are phase 2 (2 open) [5].
mce-anchor
Prostate Adenocarcinoma+
mce-anchor
Head And Neck Squamous Cell Carcinoma+
mce-anchor
Medulloblastoma+
mce-anchor
Endometrial Carcinoma+
mce-anchor
Melanoma-
PTEN is altered in 8.17% of melanoma patients with PTEN Loss present in 2.39% of all melanoma patients [4].
PTEN Loss is an inclusion criterion in 6 clinical trials for melanoma, of which 4 are open and 2 are closed. Of the trials that contain PTEN Loss and melanoma as inclusion criteria, 2 are phase 1 (0 open), 3 are phase 1/phase 2 (3 open), and 1 is phase 2 (1 open) [5].
mce-anchor
Colorectal Carcinoma+
mce-anchor
Primary Peritoneal Carcinoma+
mce-anchor
Squamous Cell Lung Carcinoma+
mce-anchor
Fallopian Tube Carcinoma+
mce-anchor
Glioblastoma-
PTEN is altered in 37.66% of glioblastoma patients with PTEN Loss present in 7.24% of all glioblastoma patients [4].
PTEN Loss is an inclusion criterion in 4 clinical trials for glioblastoma, of which 2 are open and 2 are closed. Of the trials that contain PTEN Loss and glioblastoma as inclusion criteria, 2 are phase 1 (1 open) and 2 are phase 1/phase 2 (1 open) [5].
mce-anchor
Small Cell Lung Carcinoma+
mce-anchor
Non-Hodgkin Lymphoma+
mce-anchor
Adenocarcinoma Of The Gastroesophageal Junction+
mce-anchor
Gastric Carcinoma+
mce-anchor
Urothelial Carcinoma+
mce-anchor
Pancreatic Adenocarcinoma+
mce-anchor
Medulloblastoma, Non-WNT/Non-SHH+
mce-anchor
Osteosarcoma+
mce-anchor
Soft Tissue Sarcoma+
mce-anchor
Gastric Adenocarcinoma+
mce-anchor
Clear Cell Renal Cell Carcinoma+
mce-anchor
Leiomyosarcoma+
mce-anchor
Malignant Glioma+
mce-anchor
Undifferentiated Pleomorphic Sarcoma+
mce-anchor
Chondrosarcoma+
mce-anchor
Cancer+
mce-anchor
Hepatocellular Carcinoma+
mce-anchor
Ewing Sarcoma+
mce-anchor
Head And Neck Carcinoma+
mce-anchor
Central Nervous System Embryonal Neoplasm+
mce-anchor
Esophageal Carcinoma+
mce-anchor
Gastrointestinal Stromal Tumor+
mce-anchor
Cholangiocarcinoma+
mce-anchor
Renal Cell Carcinoma+
mce-anchor
Pancreatic Carcinoma+
mce-anchor
Central Nervous System Ganglioneuroblastoma+
mce-anchor
Central Nervous System Neuroblastoma+
mce-anchor
Desmoplastic/Nodular Medulloblastoma+
mce-anchor
Large Cell/Anaplastic Medulloblastoma+
mce-anchor
Medulloblastoma With Extensive Nodularity+
mce-anchor
Medulloblastoma, SHH-Activated+
mce-anchor
Medulloblastoma, WNT-Activated+
mce-anchor
Medulloepithelioma+
mce-anchor
Multiple Myeloma+
mce-anchor
Pleomorphic Rhabdomyosarcoma+
mce-anchor
Pancreatic Ductal Adenocarcinoma+
mce-anchor
Diffuse Glioma+
mce-anchor
High-Grade Glioma, NOS+
mce-anchor
Pleomorphic Liposarcoma+
mce-anchor
Malignant Peripheral Nerve Sheath Tumor+
mce-anchor
Rhabdomyosarcoma+
mce-anchor
Oropharyngeal Squamous Cell Carcinoma+
mce-anchor
Cervical Carcinoma+
mce-anchor
B-Cell Non-Hodgkin Lymphoma+
mce-anchor
Malignant Intestinal Neoplasm+
mce-anchor
Colorectal Adenocarcinoma+
mce-anchor
High Grade Ovarian Serous Adenocarcinoma+
mce-anchor
Lymphoma+
mce-anchor
Malignant Ovarian Epithelial Tumor+
mce-anchor
Malignant Mesothelioma+
mce-anchor
Anaplastic Astrocytoma+
mce-anchor
Malignant Small Intestinal Neoplasm+
mce-anchor
Hematologic And Lymphocytic Disorder+
mce-anchor
Malignant Gastric Neoplasm+
mce-anchor
Esophageal Adenocarcinoma+
mce-anchor
Uveal Melanoma+
mce-anchor
Malignant Esophagogastric Neoplasm+
mce-anchor
Mesothelioma+
mce-anchor
Liposarcoma+
mce-anchor
Ampulla Of Vater Carcinoma+
mce-anchor
Biliary Tract Carcinoma+
mce-anchor
Hematopoietic And Lymphoid Malignancy+
mce-anchor
Neuroblastoma+
mce-anchor
Hematopoietic And Lymphoid System Neoplasm+
mce-anchor
Bile Duct Adenocarcinoma-
PTEN is altered in 1.96% of bile duct adenocarcinoma patients with PTEN Loss present in 0.24% of all bile duct adenocarcinoma patients [4].
PTEN Loss is an inclusion criterion in 1 clinical trial for bile duct adenocarcinoma, of which 1 is open and 0 are closed. Of the trial that contains PTEN Loss and bile duct adenocarcinoma as inclusion criteria, 1 is phase 1/phase 2 (1 open) [5].
mce-anchor
Thyroid Gland Carcinoma+
mce-anchor
Myeloid Neoplasm+
mce-anchor
Aggressive Systemic Mastocytosis+
mce-anchor
Anaplastic Astrocytoma, IDH-Mutant+
mce-anchor
Anaplastic Ependymoma+
mce-anchor
Anaplastic Oligodendroglioma+
mce-anchor
Anaplastic Oligodendroglioma, IDH-Mutant And 1p/19q-Codeleted+
mce-anchor
Anaplastic Pleomorphic Xanthoastrocytoma+
mce-anchor
Angiosarcoma+
mce-anchor
Atypical Teratoid/Rhabdoid Tumor+
mce-anchor
Bannayan Syndrome+
mce-anchor
Breast Lobular Carcinoma In Situ+
mce-anchor
Classical Hodgkin Lymphoma+
mce-anchor
Cowden Syndrome-
PTEN Loss is an inclusion criterion in 1 clinical trial for cowden syndrome, of which 1 is open and 0 are closed. Of the trial that contains PTEN Loss and cowden syndrome as inclusion criteria, 1 is phase 1/phase 2 (1 open) [5].
mce-anchor
Desmoid-Type Fibromatosis-
PTEN Loss is an inclusion criterion in 1 clinical trial for desmoid-type fibromatosis, of which 1 is open and 0 are closed. Of the trial that contains PTEN Loss and desmoid-type fibromatosis as inclusion criteria, 1 is phase 1/phase 2 (1 open) [5].
mce-anchor
Diffuse Midline Glioma, H3 K27M-Mutant-
PTEN Loss is an inclusion criterion in 1 clinical trial for diffuse midline glioma, H3 K27M-mutant, of which 1 is open and 0 are closed. Of the trial that contains PTEN Loss and diffuse midline glioma, H3 K27M-mutant as inclusion criteria, 1 is phase 1 (1 open) [5].
mce-anchor
Embryonal Tumor With Multilayered Rosettes, C19MC-Altered+
mce-anchor
Embryonal Tumor With Multilayered Rosettes, Not Otherwise Specified+
mce-anchor
Ependymoma+
mce-anchor
Ependymoma, RELA Fusion-Positive+
mce-anchor
Extraskeletal Osteosarcoma+
mce-anchor
Hereditary Breast And Ovarian Cancer Syndrome+
mce-anchor
Histiocytic And Dendritic Cell Neoplasm+
mce-anchor
Intracranial Primitive Neuroectodermal Neoplasm+
mce-anchor
Low Grade Ovarian Serous Adenocarcinoma+
mce-anchor
Mast Cell Leukemia+
mce-anchor
Myelodysplastic Syndromes+
mce-anchor
Myxofibrosarcoma+
mce-anchor
Myxoid Liposarcoma+
mce-anchor
Ovarian Clear Cell Adenocarcinoma+
mce-anchor
Pecoma+
mce-anchor
Peritoneal Mesothelioma+
mce-anchor
Pineoblastoma+
mce-anchor
Proteus Syndrome