LY2780301 / Eli Lilly - LARVOL DELTA

Reduction of Buchnera with rifampicin impairs the density-dependent induction of winged morph in pea aphid. (PubMed, Insect Sci) - "Wing dimorphism is a critical trait that helps insects better adapt to environments. Application of FOXO phosphorylation inhibitor LY2780301 decreased the proportion of winged aphids, while the agonist SC79 increased the proportion of winged aphids. These results revealed that reduction of Buchnera sharply declined the proportion of winged aphids, indicating that the vertical transmission of Buchnera could bring on a maternal signal of crowding perception, which was required for the production of winged offspring."

Journal

Klotho Mitigates Indoxyl Sulfate-Induced Oxidative Stress through Modulation of the AKT/Nrf2 Pathway (KIDNEY WEEK 2024) - "Blocking AKT/Nrf2 signaling with an AKT inhibitor (LY2780301) or silencing Nrf2 impeded klotho's rescue effect on HO-1 and NQO1 expression, suggesting that IS inhibits HO-1 and NQO1 via the klotho/AKT/Nrf2 axis... Our findings suggest that IS increases oxidative stress in HK-2 cells by elevating ROS and inhibiting antioxidant capacity, as evidenced by lower expression of HO-1, NQO1, and SOD via the Klotho/AKT/Nrf2 signaling pathway."

Oxidative stress • Chronic Kidney Disease • Nephrology • NQO1

Ba/F3 AKT engineering cell lines, a powerful platform for novel drug discovery (EORTC-NCI-AACR 2024) - "The failures of AKT inhibitors LY2780301 and Bayer's BAY1125976 demonstrate that there are significant challenges and complexities in developing AKT pathway inhibitors. Currently, the most advanced AKT inhibitor in the world is capivasertib from AstraZeneca , capivasertib is primarily used in HR+ breast cancer and triple-negative breast cancer.Our team has generated 23 Ba/F3-AKT engineered cell lines, which are useful models for in vitro and in vivo drug discovery, including nearly all clinically significant mutations, such as the common AKT1/2-E17K mutations and the rare L52R, Q79K, and D323H mutations.The Ba/F3-AKT engineered cell line can be used to develop and evaluate next-generation AKT inhibitors, as well as to explore newly acquired AKT resistance mutations."

Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT2 • PIK3CA • PTEN

Ba/F3 AKT engineering cell lines, a useful platform for novel drug discovery (AACR 2024) - "The failures of AKT inhibitors LY2780301 and Bayer's BAY1125976 demonstrate the significant challenges and complexities in developing inhibitors of the AKT pathway. Currently, the most advanced AKT inhibitor globally is AstraZeneca's capivasertib, which is primarily indicated for HR+ breast cancer and triple-negative breast cancer. Our group has generated 21 Ba/F3-AKT engineering cell lines, as useful models for novel drug discovery in vitro and in vivo, almost all clinically significant mutations were included, such as common mutations AKT1/2-E17K as well as rare mutations L52R, Q79K, D323H, and others. The Ba/F3-AKT engineering cell lines can be useful for developing and evaluating next-generation AKT inhibitors and exploring newly acquired resistance mutations in AKT."

Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT2 • PIK3CA • PTEN

Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study. (PubMed, Mol Oncol) - P1/2 | "In conclusions, ctDNA detection at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma-based copy number analysis may help to identify alterations involved in resistance to treatment."

Circulating tumor DNA • Journal • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • AKT1 • HER-2 • RPS6 • TP53

TAKTIC: A prospective, multicentre, uncontrolled, phase IB/II study of LY2780301, a p70S6K/AKT inhibitor, in combination with weekly paclitaxel in HER2-negative advanced breast cancer patients. (PubMed, Eur J Cancer) - P1/2 | "Combining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup."

Clinical • Combination therapy • Journal • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Infectious Disease • Oncology • Pain • Pneumonia • Respiratory Diseases • Solid Tumor • Triple Negative Breast Cancer • HER-2 • RPS6

TAKTIC: A prospective, multicenter, uncontrolled, phase IB/II study of LY2780301 (LY) in combination with weekly paclitaxel (wP) in HER2-negative locally advanced (LA) or metastatic breast cancer (MBC) patients. (ASCO 2019) - P1/2; "Combining LY and wP in HER2-negative LA or MBC was feasible with preliminary evidences of efficacy, independently of PI3K/AKT activation. Clinical trial information: NCT01980277"

Clinical • Combination therapy • P1/2 data

Phase Ib/II Study of LY2780301 in Combination With Weekly PACLITAXEL in HER2-metastatic Breast Cancer (clinicaltrials.gov) - P1/2; N=68; Recruiting; Sponsor: Institut Paoli-Calmettes; Not yet recruiting -> Recruiting

Enrollment open • Biosimilar • Breast Cancer • Oncology • Triple Negative Breast Cancer

First-in-human phase I study of LY2780301, an oral P70S6K/AKT inhibitor, in patients with refractory solid tumors (ASCO 2012) - Presentation time: Sunday June 3, 9:45 AM to 12:45 PM; P1, N=32; 13127; LY2780301 displayed favorable safety profile, and high PK exposures in the range of efficacious dose; The recommended dose will be defined in the range between 300 and 500 mg; Best response observed was prolonged SD for 6.5 cycles; Plasma exposures of LY278030 exceeded predicted efficacious dose in all pts (AUC 0-24H >25000 ng*hr/mL)

P1 data • Oncology

TAKTIC: Phase Ib/II Study of LY2780301 in Combination With Weekly PACLITAXEL in HER2-metastatic Breast Cancer (clinicaltrials.gov) - P1/2; N=68; Terminated; Sponsor: Institut Paoli-Calmettes; Active, not recruiting ➔ Terminated; Drug development stopped

Clinical • Combination therapy • Trial termination