First‐in‐human trial of the PI3Kβ‐selective inhibitor SAR260301 in patients with advanced solid tumors

Bédard, Philippe L.; Davies, Michael A.; Kopetz, Scott; Juric, Dejan; Shapiro, Geoffrey I.; Luke, Jason J.; Spreafico, Anna; Wu, Bin; Castell, Christelle; Gomez, Corinne; Cartot-Cotton, Sylvaine; Mazuir, Florent; Dubar, M.; Micallef, Sandrine; Demers, Brigitte; Flaherty, Keith T.

doi:10.1002/cncr.31044

Cited by 30 publications

(16 citation statements)

References 21 publications

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“…INK1117 is another p110α‐specific inhibitor in early phase development . Specific p110β inhibitors such as GSK2636771, AZD8186 and SAR260301 have also been tested in phase I trials in patients with advanced solid tumors including NSCLC. Taselisib (GDC‐0032) is a PI3K inhibitor that inhibits the p110α, p110γ and p110δ isoforms, but spares the p110β isoform.…”

Section: Clinical Trials Of Pi3k/akt/mtor Inhibitors In Nsclcmentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

2020

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The traditional classification of lung cancer into small cell lung cancer and non‐small cell lung cancer (NSCLC) has been transformed with the increased understanding of the molecular alterations and genomic biomarkers that drive the development of lung cancer. Increased activation of the phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway leads to numerous hallmarks of cancer and this pathway represents an attractive target for novel anticancer therapies. In NSCLC, the PI3K/Akt/mTOR pathway has been heavily implicated in both tumorigenesis and the progression of disease. A number of specific inhibitors of PI3K, Akt and mTOR are currently under development and in various stages of preclinical investigation and in early phase clinical trials for NSCLC. Early evidence has yielded disappointing results. Clinical trials, however, have been performed on predominantly molecularly unselected populations, and patient enrichment strategies using high‐precision predictive biomarkers in future trials will increase the likelihood of success. A greater understanding of the underlying molecular biology including epigenetic alterations is also crucial to allow for the detection of appropriate biomarkers and guide combination approaches.

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Section: Clinical Trials Of Pi3k/akt/mtor Inhibitors In Nsclcmentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

2020

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“…Nevertheless, clinical evaluation has not progressed beyond phase 1 for either drug. SAR260301 was unable reduce AKT signaling due to rapid clearance (determined by an ex vivo platelet p-AKT-inhibition assay) (NCT01673737) [ 174 ], and AZD6482 has not been followed up clinically in an anti-tumor setting since its initial phase 1 safety and tolerability study performed >10 years ago (NCT00688714). The p110β isoform-specific PI3K inhibitor TGX-221 and its analogue BL140 have also both shown efficacy in preclinical models of prostate cancer with PTEN loss [ 175 , 176 , 177 , 178 , 179 ], and BL140 is also reported to overcome resistance to enzalutamide in vitro [ 179 ].…”

Section: Targeting Pten-deficient Prostate Cancermentioning

confidence: 99%

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Turnham

Bullock

Dass

et al. 2020

Cells

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Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

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“…A number of PI3Kβ selective inhibitors are currently in Phase I/II trials for PTEN-deficient cancers, including AZD8186 and GSK2636771 (Table 1) [41]. Rapid clearance of SAR260301 halted its clinical development [42].…”

Section: Introductionmentioning

confidence: 99%

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Miller

Thompson²,

Gabelli

2019

Biomolecules

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Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

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First‐in‐human trial of the PI3Kβ‐selective inhibitor SAR260301 in patients with advanced solid tumors

Cited by 30 publications

References 21 publications

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

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