Abstract PD4-14: GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies

Abstract

The phosphatidylinositol 3 kinase (PI3K)/AKT/ mechanistic target of rapamycin (mTOR) signaling pathway is a major regulator of tumor cell growth, proliferation and survival. Dysregulation of the PI3K/AKT/mTOR signaling pathway through multiple different mechanisms has been described in solid tumor malignancies, including activating and transforming mutations and amplification of PIK3CA, that encodes the p110alpha subunit of PI3K. Indeed, PIK3CA hotspot mutations are highly prevalent in breast cancer, occurring in approximately 40% of HR+ tumors. The clinical candidate GDC-0077 is a potent inhibitor of PI3Kalpha (IC50 = 0.038 nM) and exerts its activity by binding to the ATP binding site of PI3K, thereby inhibiting the phosphorylation of PIP2 to PIP3. Biochemically, GDC-0077 is >300-fold more selective for PI3Kalpha over the other class I PI3K isoforms (beta, delta, and gamma) and >2000-fold more selective over PIK family members. Furthermore, GDC-0077 is more selective for mutant versus wild-type PI3Kalpha in cell based assays. The improved biochemical selectivity of GDC-0077 relative to PI3Kdelta translated in human CD69+ B-cells, which are primarily dependent on PI3Kdelta for proliferation and survival, and were more sensitive (based on reduction of cell number) to the PI3Kalpha/delta selective inhibitor taselisib (GDC-0032) than to GDC-0077. Mechanism of action (MOA) studies indicate that GDC-0077 selectively degrades mutant PI3Kalpha in a proteasome-dependent fashion resulting in reduction of PI3K pathway activity biomarkers such as pAKT and pPRAS40, inhibition of cell proliferation, and increased apoptosis in human PIK3CA-mutant breast cancer cell lines to a greater extent when compared to PIK3CA wild-type cells. In vivo, oral daily treatment of patient-derived PIK3CA-mutant breast cancer xenograft models with GDC-0077 resulted in tumor regressions, induction of apoptosis, and a reduction of pAKT, pPRAS40, and pS6RP in a dose-dependent fashion. In vivo efficacy in a PIK3CA-mutant human breast cancer xenograft model was also improved when GDC-0077 was combined with therapies for hormone-receptor positive (HR+) breast cancer such as anti-estrogens (fulvestrant) or a CDK4/6 inhibitor (palbociclib). Collectively, preclinical studies provide rationale for evaluating GDC-0077, a PI3Kalpha selective inhibitor that degrades mutant p110alpha protein, as a single agent and in combination with endocrine and targeted therapies that may provide additional benefit to patients with locally advanced or metastatic hormone receptor+ breast cancers that harbor PIK3CA mutations. Citation Format: Hong R, Edgar K, Song K, Steven S, Young A, Hamilton P, Arrazate A, De La Cruz C, Chan C, Pang J, Salphati L, Belvin M, Nannini M, Staben S, Friedman L, Sampath D. GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-14.

Efficacy of PI3K inhibitors in advanced breast cancer

“…GDC-0077 is a potent, orally available, and selective PI3Kα inhibitor (IC50=0.038 nM) that has demonstrated robust efficacy in PIK3CA -mutant breast cancer models [89]. Compared to the PI3K inhibitor, taselisib, the improved biochemical selectivity of GDC-0077 against PI3K delta is demonstrated in human CD69+ B-cells, which are primarily dependent on PI3K delta for proliferation and survival and were more sensitive to taselisib than GDC-0077.…”

Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors

“…We speculate that the prominent gastrointestinal side effects could have been secondary to inhibition of p110δ as it has been seen in trials with the p110δ inhibitors idelalisib and copanlisib (35,36) and may have compromised selective inhibition of mutant PIK3CA in primary tumors in vivo. Another clinical candidate is the ATP mimetic GDC-0077, with more than 300-fold selectivity against p110α (IC 50 0.038 nmol/L) over the β, γ, and δ class I PI3K isoforms (64). GDC-0077, which also selectively degrades mutant PI3K, has shown remarkable preclinical activity against PIK3CAmutant breast cancer cells and PDXs (64).…”

“…Another clinical candidate is the ATP mimetic GDC-0077, with more than 300-fold selectivity against p110α (IC 50 0.038 nmol/L) over the β, γ, and δ class I PI3K isoforms (64). GDC-0077, which also selectively degrades mutant PI3K, has shown remarkable preclinical activity against PIK3CAmutant breast cancer cells and PDXs (64). GDC-0077 is now in early clinical development as a single agent and in combination with endocrine and other targeted therapies in patients with advanced breast cancer who harbor PIK3CA mutations.…”

Personalized Medicine: Recent Progress in Cancer Therapy

“…Mechanism of Action Phase PI3K inhibitors GDC0077 [41] Potent PI3K alpha inhibitor Ib MEN1611 (PA799) [42] PI3K alpha inhibitor Ib AMG319 [43] AMG319 is a PI3Kδ inhibitor. Preclinically, target inhibition abrogates Treg-mediated immunosuppression, augmenting CD8+ T-cell antitumor activity Activation of fibroblast growth factor receptor (FGFR) pathways also plays a major role.…”