Nav: Home

Oncotarget Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy

March 18, 2020

The cover for issue 11 of Oncotarget features Figure 6, "Effects of AZD8186 in combination with anti-PD1 on syngeneic models," by Owusu-Brackett, et al.

In vitro cell viability assay and immunoblotting demonstrated that PTEN loss was significantly correlated with AZD8186 sensitivity in triple-negative breast cancer cell lines.

AZD8186 in combination with paclitaxel, eribulin had synergistic effects on growth inhibition in PTEN loss cells.

AZD8186 significantly enhanced the antitumor efficacy of anti-PD1 antibodies in the PTEN-deficient BP murine melanoma xenograft model, but not in the PTEN-wild-type CT26 xenograft model.

In vitro, cell proliferation and colony formation assays were performed to determine cell sensitivity to AZD8186.

AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro but has limited single-agent efficacy in vivo.

Dr. Funda Meric-Bernstam from the Department of Surgical Oncology, the Department of Investigational Cancer Therapeutics, the Department of Breast Surgical Oncology, as well as The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center, in Houston, Texas, USA said, "Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell."

"Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell."

- Dr. Funda Meric-Bernstam, Department of Investigational Cancer Therapeutics, the Department of Breast Surgical Oncology & The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy

Mutations, loss of copy number, epigenetic silencing and downregulation of PTEN protein by mi RNA can result in PTEN function inactivation, leading to activation of PI3K/AKT/mTOR pathway, which subsequently increases tumor growth, invasion and metastasis across a diverse set of solid tumors including breast, endometrial, prostate, renal cell, hepatocellular, glioblastoma, and colorectal cancers.

Loss of PTEN and increased PI3K signaling are associated with resistance to trastuzumab and endocrine therapy in hormone receptor-positive breast cancer and with poor prognosis in triple-negative breast cancers.

In vitro, they revealed significant growth inhibition of PTEN-deficient tumors by depleting PIK3CB which encodes PI3K, while no such growth inhibition effect was shown in corresponding PTEN-deficient tumors with downregulation of PIK3CA or PIK3CD encoding PI3K and PI3K, respectively.

Thus, PI3K isoform is the driver of abnormal proliferation in PTEN-null cancers, and as such, PI3K is a promising target for therapy in PTEN-deficient TNBC. AZD8186 is a selective and potent small-molecule inhibitor of PI3K, with additional activity against PI3K isoform.

The Meric-Bernstam Research Team concluded in their Oncotarget Research Paper, "these results provide preclinical evidence of antitumor efficacy of AZD8186 in PTEN-deficient solid tumors. AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro, with modest single-agent efficacy in vivo. Furthermore, AZD8186 enhanced the antitumor efficacy of paclitaxel but stable and progressive disease were noted with this combination in immunosuppressed models. In immunocompetent models, AZD8186 in combination with anti-PD1 resulted in tumor regression in PTEN-deficient BP tumor. We realize that while there appears to be an association of AZD8186 sensitivity to PTEN loss, a cause-effect relationship can only be speculated on. In summary, although further insights are needed into the mechanisms of activity of these combinations, the combination of AZD8186 with taxanes and with anti-PD1 agents hold promise for the treatment of PTEN-deficient solid tumors."

Sign up for free Altmetric alerts about this article

DOI - https://doi.org/10.18632/oncotarget.27503

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=27503&path%5B%5D=90086Correspondence to - Funda Meric-Bernstam - fmeric@mdanderson.org

Impact Journals LLC

Related Antitumor Efficacy Articles:

Intralipid improves efficacy of chemotherapy treatment
Pairing chemotherapy nanodrugs with a nutritional supplement can lessen devastating side-effects while reducing the amount of the expensive drugs needed to treat cancer according to a study from Carnegie Mellon University and Taiwan's National Health Research Institutes.
AI Therapeutics announces that a common LAM-002 mechanism in cancer and neurodegenerative diseases shows antitumor activity in the clinic and hope for ALS
AI Therapeutics has made significant recent progress with its four clinical assets and proprietary Guardian Angel™ algorithm.
Study gauges efficacy of drugs against pork tapeworm
Taenia solium -- also called pork tapeworm -- is a parasite which causes disease around the world, particularly in very poor communities with deficient sanitation and where pigs roam free.
FEFU scientists obtained new compounds with potential antitumor effect from sea sponge
Chemists from Far Eastern Federal University's School of Natural Sciences (SNS FEFU) developed a new method to synthesize biologically active derivatives of fascaplysin -- cytotoxic pigment of a sea sponge.
Identifying the efficacy of treating encephalitis in leukemia therapy
Revealing the mechanism of glial cell activity...expected to be used for treatment of dementia
Discovered a new process of antitumor response of NK cells in myeloma
The stem cell transplant and cell immunotherapy group of the Josep Carreras Leukemia Research Institute reveals how NK cells activate a set of actions that promote their antitumor capacity in the presence of myeloma cells.
Hormonal contraceptives affect the efficacy of exposure therapy
Psychologists at Ruhr-Universität Bochum have studied in what way hormonal contraceptives affect the efficacy of anxiety therapy.
Mauritian medical herbs possess antitumor properties
Far Eastern Federal University (FEFU) scientists teamed up with colleagues from the UK and Mauritius and experimentally demonstrated that extracts of the endemic (i.e. growing only on this island) medicinal herb leaves Acalypha integrifolia, Eugenia tinifolia, and Labourdonnaisia glauca stop the proliferation of esophageal squamous carcinoma cells, ones of the most deadly cancer type worldwide.
HER2-targeted CAR T-cell therapy shows promising antitumor activity in patients with sarcoma
A combination of chemotherapy and chimeric antigen receptor (CAR) T cells designed to target the protein HER2 was found to be safe and showed clinical responses in pediatric and adult patients with advanced HER2-positive sarcoma, according to results from a phase I clinical trial presented at the AACR Annual Meeting 2019, March 29-April 3.
How well do vaccines work? Research reveals measles vaccine efficacy
'What we found was a bit of a shock -- there are a very small number of studies that test whether vaccines are effective across multiple pathogen doses ...' said Langwig.
More Antitumor Efficacy News and Antitumor Efficacy Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.