Abstract 3721: MTORC1/2 and HDAC1/2 inhibition as therapy for colorectal cancer with PIK3CA mutation
Authors: Olson Autumn M. , DeStefanis Rebecca A. , DeZeeuw Alyssa K. , Payne Susan N. , Pasch Cheri A. , Clipson Linda , Deming Dustin A. 
Published: June 2022

Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths. PIK3CA mutations are found in 18% of CRCs which lead to the constitutive activation of the PI3K/MTOR pathway and can promote tumorigenesis. Here, we examine the efficacy of the FDA approved inhibitors copanlisib, a PI3K/MTOR inhibitor, and romidepsin, a HDAC1/2 inhibitor, in CRC with a PIK3CA mutation.

Methods: CRC mouse derived cancer organoids (MDCOs) were derived from Apc and Pik3ca mutant mice (Fc1Apcfl/+Pik3caH1047R/+). Brightfield images of the MDCOs were taken prior to treatment with copanlisib, romidepsin, or the combination and 48 hours post-treatment. The change in diameter of each organoid over the 48-hour treatment was determined. Additionally, immunoblotting was performed to confirm known targets of copanlisib and romidepsin were altered in response to drug treatment. MTORC1/2 and HDAC1/2 inhibition were also investigated in vivo. SW48 and SW48PIK3CA-H1047R (SW48PK) xenograft mice were treated with a vehicle control, copanlisib, romidepsin, or the combination therapy.

Results: In the diameter analysis study, the combination therapy had the largest effect size compared to control (Glass’s Δ 2.82). Single agents copanlisib and romidepsin had smaller effect sizes (Glass’s Δ 1.75 and 2.04, respectively). Immunoblotting results indicated a decrease in phosphoAKT (Ser473) and pRPS6 (Ser235/236) in the copanlisib treated samples and an increase in H3K27 acetylation was seen in the romidepsin treated samples. There was also increased cleaved PARP, an indicator of apoptosis, in the romidepsin and combination therapy treatment groups. In vivo, SW48 xenografts showed a greater response in the combination therapy compared to either single agent therapy (median relative change in tumor volume: control=339%; combination therapy=107%(p-value&lt;0.05), copanlisib=225%(p-value=0.17), romidepsin=200%). A similar trend was seen in the SW48PK xenograft mice (median relative change in tumor volume: control=241%; combination therapy=70% (p-value&lt;0.05), copanlisib=132%(p-value&lt;0.05), romidepsin=177%).

Conclusion: MDCOs with Apc and Pik3ca mutations had an increased response to treatment with the combination therapy as compared to the single agents alone. Additionally, in vivo studies with human CRC xenografts showed enhanced inhibition of tumor growth with both MTORC1/2 and HDAC1/2 inhibition. These data demonstrate potential for this combination treatment strategy for the treatment of PIK3CA mutant CRC and this combination warrants further investigation in other models and clinically.

Citation Format: Autumn M. Olson, Rebecca A. DeStefanis, Alyssa K. DeZeeuw, Susan N. Payne, Cheri A. Pasch, Linda Clipson, Dustin A. Deming. MTORC1/2 and HDAC1/2 inhibition as therapy for colorectal cancer with PIK3CA mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3721.