Abstract 675: First-in-class approved phosphoinositide-3-kinase inhibitor Alpelesib (BYL 719): Examination of disease-specific activity in human tumor 3 dimensional primary culture organoids
Authors: Robert Alan Nagourney, Adam J. Nagourney, Peter Tran, Paula Bernard, Federico Francisco, Steven S. Evans
Journal: Cancer Research (2020)

Abstract Phosphoinositide 3-kinases (PI3Ks) are hetero-dimeric lipid kinases that are frequently dysregulated in cancer. Class I PI3K activity is upregulated in many breast cancers via mutations in PIK3CA, PIK3R1, PTEN and AKT1 making PI3K inhibition attractive as a therapeutic target. BYL719, an oral α-specific PI3K inhibitor that selectively inhibits p110α was granted FDA approval for estrogen receptor (ER) + breast cancer following the successful completion of the SOLAR-1 trial (Andre, F. et al NEJM, 2019). To explore the clinical utility of BYL 719 in human cancer, we applied the Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) in surgical specimens obtained from 388 individual patients. Methods: EVA/PCD technique uses enzymatic and mechanical disaggregation followed by density centrifugation to isolate human tumor 3-D organoids of desired size. Morphologic and metabolic measures of cell death provide lethal concentration 50% (LC50), interpolated from 5-point dose response curves and then compared by modified Z-score to provide disease-specific activity. BYL 719 correlations with other classes of drugs are performed by Pearson Moment with significance by two tailed T-test. Results: By rank order the highest BYL719 activity was found in Uterine&amp;gt;Breast&amp;gt;Colon&amp;gt;Gastric&amp;gt;Ovary&amp;gt; Pancreas. The lowest BYL719 activity was found for Melanoma&amp;lt;Heme&amp;lt;GBM&amp;lt;Neuroendocrine&amp;lt;Sarcoma&amp;lt;NSCLC. Drug correlations were significant (Bonferroni-correction) for Idelalisib, Pictilisib, BEZ 235 and Everolimus as well as Gefitinib, Lapatinib, Selumetinib and Palbociclib. Among cytotoxic agents tested BYL719 activity only correlated with CDDP and 5FU. Conclusions: Whilst BYL 719 has been FDA approved for ER (+) breast cancer, our results suggest a strong rationale for its use in uterine cancer. As uterine cancer is associated with mutations in PTEN and PI3K, the BYL719 activity identified by EVA/PCD is highly consistent with the known molecular profiles. In an analysis of 87 breast cancer specimens, by subgroup (ER, PR, HER2, BRCA, etc.) only previously untreated patients revealed significantly higher BYL 719 activity. Based upon mechanism of action, correlations with PIK3 and PTEN inhibitors are expected, but those with EGFR, HER2 and CK 4/6 inhibitors may offer insights into potential synergies currently being evaluated by EVA/PCD. Discussion: BYL719's approval marks the introduction of a new drug class into clinical therapy. With a growing number of small molecule signal transduction inhibitors, the capacity to target PIK3 offers the opportunity to forge new drug combinations. The EVA/PCD platform's capacity to examine disease-specific activity and drug synergy offers the opportunity to streamline drug development, accelerate the introduction of new classes of agents and explore novel drug combinations. Citation Format: Robert Alan Nagourney, Adam J. Nagourney, Peter Tran, Paula Bernard, Federico Francisco, Steven S. Evans. First-in-class approved phosphoinositide-3-kinase inhibitor Alpelesib (BYL 719): Examination of disease-specific activity in human tumor 3 dimensional primary culture organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 675.