Abstract 2051: PAT-1102, a novel HDAC inhibitor exhibits potent anti-tumor efficacy in patient-derived refractory solid tumors.
Authors: Radhakrishnan Padhma , Dhandapani Muthu , Ulaganathan Baraneedharan , Thayakumar Allen , Thiyagarajan Saravanan , Pinto Dency , Vinod D R. , Majumder Biswanath , Shivarudriaah Prasad , Jagadheshan H , Sambasivam Ganesh , Majumder Pradip K. 
Published: August 2014

Histone deacetylases (HDAC) have been shown to be involved in oncogenic transformation by mediating transcription factors. Although a few HDAC inhibitors (HDACi) have been shown to be effective in patients with rare leukemia, there is a need to develop best in class HDACi with higher therapeutic index in solid cancers. PAT-1102 is a novel HDACi that exhibited potent histone deacetylase inhibitory activity and growth inhibitory activity against a panel of cell lines in in vitro and in vivo models. Studies indicated that PAT-1102 mediates target modulation (histone hyperacetylation), p21 up regulation, angiogenesis inhibition, and induction of cell cycle arrest in these models. PAT-1102 possesses drug like properties including good aqueous solubility, oral absorption, metabolic stability and favorable pharmacokinetic profile in rodents. It did not show any hERG inhibitory activity, CYP liability and was well tolerated in tumor bearing mice. It had showed a dose dependent tumor growth inhibition of up to 72% in cell line based xenograft models of lung and colorectal cancer. Our data further indicated that the anti-tumor efficacy of PAT-1102 was superior to Vorinostat and comparable with Pracinostat (SB-939) while being more tolerable than Pracinostat. Although it has pan histone deacetylase properties, it showed preferential inhibition of HDAC-3 & HDAC-6.

PAT-1102 efficacy was further assessed using “Oncoprint®” platform, a clinically relevant preclinical technology that has been demonstrated to have very high correlation to clinical outcome for chemotherapeutics as well as targeted drugs in multiple solid and hematological cancers (with overall sensitivity of 88% and specificity of 90% in N=500+ patients). Using Oncoprint®, PAT-1102’s efficacy was assessed in patient derived solid cancers (Pancreas, Gastric, Esophagus, Head & Neck, and Colorectal). Further we assessed the efficacy of PAT-1102 alone as well as in combination with various Standard-Of-Care drugs (SOCs) and compared the outcome with efficacy derived from the use of SOCs alone. Our study has been powered to include 75-100 patient derived refractory/recurrent tumors in each indication. Current results indicated the superiority of PAT-1102 when combined with SOCs in a subset of patients with solid cancers. Pre-clinical data shows that PAT-1102 has no toxic effect when given alone or in combination with SOC at efficacious doses . PAT-1102 has the potential to be more effective in a defined patient population than other molecules in this class.

In summary, we have identified a novel, potent HDACi with drug like properties. Our data suggest PAT-1102 has the potential to be best in class HDACi when combined with SOC in solid cancers. Clinical development of PAT-1102 in solid cancers will be initiated in 2013.

Citation Format: Padhma Radhakrishnan, Muthu Dhandapani, Baraneedharan Ulaganathan, Allen Thayakumar, Saravanan Thiyagarajan, Dency Pinto, D R. Vinod, Biswanath Majumder, Prasad Shivarudriaah, H Jagadheshan, Ganesh Sambasivam, Pradip K. Majumder. PAT-1102, a novel HDAC inhibitor exhibits potent anti-tumor efficacy in patient-derived refractory solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2051. doi:10.1158/1538-7445.AM2013-2051