A texaphyrin-oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells
作者: Arambula, Jonathan F. ; Sessler, Jonathan L. ; Siddik, Zahid H.
A texaphyrin-oxaliplatin conjugate, oxaliTEX, was designed to test the concept that a platinum analog can overcome defects in drug accumulation and p53-dependent DNA damage response in a tumor model expressing multifactorial mechanisms of cisplatin resistance. Cytotoxic studies resulted in a resistance factor of only 1.2, which essentially indicated complete reversal of resistance in 2780CP cells expressing a factor of 22 with cisplatin. Unlike cisplatin, oxaliTEX accumulated and formed DNA adducts, stabilized and activated p53 at similar levels in both sensitive and resistant cells, and induced apoptosis in both models. The ability and importance of a designer drug, such as oxaliTEX, to overcome cisplatin resistance by targeting two dominant resistance mechanisms is discussed.
AUSTIN, Texas, Oct. 7, 2022 /PRNewswire/ -- Traditional chemotherapies continue to demonstrate limited efficacy in drug-sensitive and drug-resistant solid tumors. InnovoTEX Inc. (InnovoTEX), an Austin-based pharmaceutical company, is developing next generation anti-cancer agents that localize to solid tumors and overcome resistance mechanisms with minimal side effects.
InnovoTEX has acquired an exclusive and perpetual license, facilitated by the Discovery to Impact group at the University of Texas at Austin, to an innovative discovery platform and corresponding patent portfolio to identify and design therapeutic candidates for a range of solid tumor indications.
InnovoTEX is developing its proprietary TEX Core platform, which utilizes the tumor-localizing and well-tolerated small molecule, texaphyrin, as the basis for a series of conjugates designed to target and treat both drug-sensitive and drug-resistant solid tumors.
The first clinical candidate to be commercialized from the platform is OxaliTEX, a novel chemical entity (WO2015/191797) in a pro-drug form. Patent applications covering both composition and methods of treatment claims for OxaliTEX have been filed in 15 global jurisdictions. Currently, OxaliTEX patents covering the core compositions have been issued in the United States, Australia, Israel, South Korea, Mexico and Singapore.
Pre-clinical research conducted at the University of Texas at Austin and MD Anderson Cancer Center has demonstrated oncolytic activity in multiple indications. OxaliTEX was found to completely inhibit the tumor growth in platinum-resistant patient derived xenografts and result in extended survival of ovarian and colon cancer models. Platinum-resistant ovarian cancer is the planned lead indication for OxaliTEX.
"From the preclinical data generated, OxaliTEX has displayed greater efficacy and tolerability against advanced human cancer models compared to traditional chemotherapies. We are optimistic that OxaliTEX's therapeutic benefits will translate well to the clinic with further development," InnovoTEX CEO, Dr. Jonathan Arambula said.
Professor Jonathan Sessler, R.P. Doherty, Jr. – Welch Regents Chair in Chemistry at the University of Texas at Austin, partnered with Dr. Arambula and Dr. Zahid Siddik at MD Anderson Cancer Center, in developing technologies that led to OxaliTEX.
"I am excited to see this technology moving to the next level of development and advancing to the clinic for the treatment of a disease for which our current therapeutic options are still unsatisfactory," Professor Sessler said.
Research was generously funded by multiple institutions, including the Cancer Prevention and Research Institute of Texas, the National Institutes of Health and the Robert A. Welch Foundation.