Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

Background In phase III SOLAR-1 trial (NCT02437318), the PI3K alpha selective inhibitor alpelisib (ALP) + fulvestrant significantly improved progression-free survival vs. fulvestrant alone in patients with HR+/HER2- advanced breast cancer with PIK3CA mutations. Hyperglycemia is an on-target adverse effect of ALP that led to 6% of patient discontinuation in the ALP arm. Recently, Sodium-glucose co-transporter 2 (SGLT2) inhibition was reported to reduce PI3K inhibition-induced glucose and insulin increase. For 6 SOLAR-1 patients, the addition of an SGLT2 inhibitor to metformin (MET) and ALP stabilized blood glucose levels, allowing them to continue ALP treatment. Methods Brown Norway (BN) rat and Rat1-myr-p110α tumor bearing nude rat in vivo models were used to further investigate the degree of glucose and insulin control achievable upon treatment with ALP and a SGLT2 inhibitor dapagliflozin (DAPA) +/- MET and effects on ALP tolerability and efficacy. Results In both rat models tested, the addition of DAPA to ALP nearly suppressed ALP-induced hyperglycemia, was associated with insulin level reduction and insulin sensitivity improvement and no signs for ketoacidosis upon single agent (S.A) nor combination were observed under fed conditions. ALP S.A efficacy in the Rat1-myr-p110α tumor bearing nude rats was maintained when used in combination with DAPA and there was no influence of DAPA on ALP-induced body weight loss (BWL). In BN rats, when combining MET with ALP, a delay in blood glucose reduction was observed vs. DAPA + ALP combination. The triple combination of MET + DAPA + ALP improved further blood glucose levels reduction with the same kinetic as DAPA + ALP. MET + DAPA + ALP triple combination was more effective in reducing plasma insulin levels when compared to MET + ALP or DAPA + ALP double combinations. All combinations tested with MET slightly increased BYL719-induced BWL in BN rats. Conclusions SGLT2 inhibitors such as DAPA significantly reduced hyperglycemia and improved hyperinsulinemia induced by ALP in rat models without further BWL induced by ALP. These results warrant further clinical investigation of adding SGLT2 inhibitors +/- metformin to treat ALP-induced hyperglycemia. Citation Format: Christian R. Schnell, Daniel Wyss, Walter Tinetto, Thomas Ferrat, Jiaping Gao, Panza Darrell, Josh Gold, Valerie Beaulieu, John Diener, Christine Fritsch. SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P137.

No abstract

The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BYL719. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues (adipocytes and muscles). NVP-BYL719 (a selective inhibitor of the class Ia PI3K isoform alpha) given in the morning is facing on-target tolerability challenge (hyperglycemia) in clinical trials limiting the dose being administered to patient (1). As glucose metabolism is highly impacted by circadian rhythms in patients and rodents, we have decided to adopt an integrative circadian-timing approach in our pre-clinical models to interrogate the benefit of morning vs evening dosing for BYL719. By using a newly developed radio-telemetry technology (2), we were able to record in real time and 'around-the-clock' blood glucose levels in stress-free, freely moving rats dosed with NVP-BYL719 at different regimens. The dynamic profile of hyperglycemia observed after active or inactive period dosing of NVP-BYL719 (50 mg/kg qd p.o.) were similar. Dosing before the inactive phase (10 a.m.) allowed blood glucose to normalize in between 2 doses, which could not be achieved when dosing before the active phase (5 p.m.). After treatment discontinuation a significant hyperglycemia remained for a period up to 12h in the group dosed before the active phase (5 p.m.). Circadian “evening” NVP-BYL719 dosing is associated with a better control of glycaemia. Clinically this could potentially translate to better compliance and longer time on treatment hence better efficacy for patient. Based on these findings we could recommend optimized treatment schedules for future combination experiments in the clinic with NVP-BYL719. 1) Juric et al, “Phase I study of the PI3Kα Inhibitor BYL719, as a Single Agent in Patients with Advanced Solid Tumors (AST)”, Annals of Oncology (2014), 25 (Supp. 4) 2) Brockway et al, “Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months”, J Diabetes Sci Technol (2015), 9(4):771-81 Citation Format: Christian R. Schnell, Thomas Ferrat, Daniel Wyss, Walter Tinetto, Sonja Tobler, Christine Fritsch, Michael Jensen. Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3933.