A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Sarker, Debashis; Dawson, Nancy A.; Aparicio, Ana; Dorff, Tanya B.; Vaishampayan, Ulka N.; Henson, Lynn; Vasist, Lakshmi; Roy-Ghanta, Sumita; Gorczyca, Michele; York, Whitney; Ganji, Gopinath; Tolson, Jerry M.; Bono, Johann S. de

doi:10.1158/1078-0432.ccr-21-1115

Cited by 16 publications

(11 citation statements)

References 27 publications

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“…Given the effectiveness of alpelisib, other combined strategies are still in development, and toxicity management should be considered simultaneously (Rugo et al 2021 ). In a first-in-human study (NCT01219699) with 134 patients with PIK3CA -mutated solid tumours, 13.4% of patients discontinued treatment because of serious adverse events, but overall, the safety was tolerable (Juric et al 2018 ).…”

Section: The Typical Pi3k Inhibitors Approved or In Clinical Trialsmentioning

confidence: 99%

Development and safety of PI3K inhibitors in cancer

Chen

et al. 2023

Arch Toxicol

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The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches.

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Section: The Typical Pi3k Inhibitors Approved or In Clinical Trialsmentioning

confidence: 99%

Development and safety of PI3K inhibitors in cancer

Chen

et al. 2023

Arch Toxicol

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“…70 GSK2636771 is an isoform-specific inhibitor of p110β that has been tested in combination with enzalutamide in PTEN-deficient prostate cancer patients who previously progressed on enzalutamide monotherapy. 71 The most common treatment-related adverse events associated with this agent were diarrhea (56%), fatigue (22%), hypocalcemia (22%), decreased appetite (19%), nausea (17%), and blood creatinine increased (17%). One of 31 patients evaluable for radiographic response achieved a partial response lasting 36 weeks, AZD8186 has potent activity against p110β and p110δ, and has been tested as monotherapy in multiple tumor types and in combination with abiraterone in prostate cancer.…”

Section: Pi3k Isoform Specific Inhibitorsmentioning

confidence: 99%

“…GSK2636771 is an isoform‐specific inhibitor of p110β that has been tested in combination with enzalutamide in PTEN‐deficient prostate cancer patients who previously progressed on enzalutamide monotherapy 71 . The most common treatment‐related adverse events associated with this agent were diarrhea (56%), fatigue (22%), hypocalcemia (22%), decreased appetite (19%), nausea (17%), and blood creatinine increased (17%).…”

Section: Introductionmentioning

confidence: 99%

PTEN‐PI3K pathway alterations in advanced prostate cancer and clinical implications

Choudhury

2022

The Prostate

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Background: Despite significant advances in molecular characterization and therapeutic targeting of advanced prostate cancer, it remains the second most common cause of cancer death in men in the United States. The PI3K (Phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin) signaling pathway is commonly altered in prostate cancer, most frequently through loss of the PTEN (Phosphatase and Tensin Homolog) tumor suppressor, and is critical for cancer cell proliferation, migration, and survival.Methods: This study summarizes signaling through the PTEN/PI3K pathway, alterations in pathway components commonly seen in advanced prostate cancer, and results of clinical trials of pathway inhibitors reported to date with a focus on more recently reported studies. It also reviews rationale for combination approaches currently under study, including with taxanes, immune checkpoint inhibitors and poly (ADP-ribose) polymerase inhibitors, and discusses future directions in biomarker testing and therapeutic targeting of this pathway.Results: Clinical trials studying pharmacologic inhibitors of PI3K, AKT or mTOR kinases have demonstrated modest activity of specific agents, with several trials of pathway inhibitors currently in progress. A key challenge is the importance of PI3K/AKT/mTOR signaling in noncancerous tissues, leading to predictable but often severe toxicities at therapeutic doses.Conclusions: Further advances in selective pharmacologic inhibition of the PI3K/AKT/ mTOR pathway in tumors, development of rational combinations, and appropriate biomarker selection to identify the appropriate tumor-and patient-specific vulnerabilities will be required to optimize clinical benefit from therapeutic targeting of this pathway.

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“…GSK2636771 is a PI3Kβ inhibitor. The safety profile was acceptable, but the efficacy in metastatic castration‐resistant prostate cancer was limited 359 . More clinical trials are ongoing (NCT04439188 and NCT02951091).…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors targeting the cancers

Liu

Chen

Zhang

et al. 2022

MedComm

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Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.

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A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Cited by 16 publications

References 27 publications

Development and safety of PI3K inhibitors in cancer

Development and safety of PI3K inhibitors in cancer

PTEN‐PI3K pathway alterations in advanced prostate cancer and clinical implications

Small molecule inhibitors targeting the cancers

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