Abstract B49: Using small molecule activators of PP2A to negatively regulate c-myc in small cell lung cancer

Abstract

Abstract Treatment for small cell lung cancer (SCLC) is based on combination chemotherapy with a five-year survival of just 10-13% for patients with limited disease. A common molecular alteration in SCLC is the overexpression of MYC family oncogenes, occurring in 18-31% of SCLCs, and more commonly in chemo-refractory disease. Several FDA approved tricyclic antidepressants were recently shown to have efficacy in SCLC cell lines based on G-protein coupled receptor (GPCR) mediated effects, and a phase IIa trial is testing one of these compounds. A reverse chemical engineering approach was employed to remove GPCR pharmacology from the tricyclic family of compounds, generating a novel class known as SMAPs, small molecule activators of protein phosphatase 2A (PP2A). PP2A is a tumor suppressor with an established negative regulatory action on c-myc. Thus, it was hypothesized that SMAPs could represent a novel treatment approach in SCLC via activation of PP2A with downstream effects on targets including c-myc. A genetic signature score for SMAP efficacy predicted broad activity of these compounds in SCLC and identified myc family pathways as strongly correlated to IC50 in a panel of tumor cell lines. Incubation with the SMAP TRC-794 was shown to induce apoptosis in the SCLC cell lines H82 and H69 as seen by induction of annexin V as well as parp and caspace-3 cleavage. Loss of c-myc in the c-myc amplified cell line H82 was observed in a dose dependent manner at 24hrs. Loss of c-myc was observed by 6 hours of drug treatment in H82 and H2081 cells. Supporting a PP2A dependent mechanism, molecular effects on c-myc in H82 were partially reversed with the phosphatase inhibitor okadaic acid. IC50s for these cell lines were similar to those for a lung adenocarcinoma line with established in vivo sensitivity to TRC-794. TRC-1154, a more potent SMAP, was shown to produce statistically significant tumor growth inhibition compared to vehicle control in a xenograft model when orally dosed at 100mg/kg daily. In summary, SMAPs may represent a viable treatment approach in SCLC, possibly via a PP2A mediated negative regulation of c-myc. Citation Format: Benjamin Jonathan Wolpaw, Goutham Narla, Shashank Cheemalavagu. Using small molecule activators of PP2A to negatively regulate c-myc in small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B49.