Although advances in chemotherapy over the past 20 years have led to better survival of patients with various forms of cancer, the continuing biological evolution of drug-driven tumors leads to the breakdown of resistant forms with the consequent possibility of therapeutic failures. This is why the continuous development of new categories of drugs is necessary to overcome the problem. A study in a class of anticancer drugs FDA approved clinical trials, reveals that CPI-613 is effective against most carcinoma cell lines and, used in combination, could have efficacy against reducing some tumors. The research was developed at the Department of Biochemistry and Cell Biology in the Renaissance School of Medicine at Stony Brook University, through collaborative efforts in the Department of Biochemistry and Cell Biology. Cornerstone Pharmaceuticals, Inc., licensed the technology from The Research Foundation of the State University of New York in 2001, and after years of experimentation, the drug was brought to pre-clinical testing in 2011.
As the exclusive licensee, Cornerstone is conducting clinical trials of CPI-613. The drug targets cancer mitochondrial tricarboxylic acid (TCA) cycle metabolism with tumor selectivity and its mechanism of action also makes it a useful experimental probe of cancer metabolism. Clinical trials of CPI-613 have shown only some patients respond to the drug with reduction of tumors; the new research may form a new basis of using the anti-cancer agent more effectively in combination with cancer treatments, especially with difficult-to-treat tumors. Researchers have show that failures to respond to CPI-613 in clinical applications have a very simple, specific, tumor-general cause. The TCA cycle metabolizes all major nutrient classes, then feeds the electrons these processes generate into the electron transport system (ETC) to produce energy. This fatty acid “by-pass” resistance enables the scientists to target it with two well-known drugs employed for other purposes, thioridazine and crizotinib, improving CPI-613 sensitivity.
The researchers demonstrated that electron flow from fatty acids initially metabolized in the peroxisome enroute to mitochondria can bypass the CPI-613 blockade, which produces the drug resistance observed in some tumors. They further demonstrated that this resistance-producing electron flow can be targeted to substantially enhance the anticancer performance of CPI-613. Drugs to target the mitochondrial system have also been studied in the past in oncology, but they had no specificity. Almost all of them remained confined to laboratory studies to understand the biology of mitochondria. One of them, lonidamine, found use in the decade 1980-1990, but was subsequently abandoned. Unraveling the complex biochemistry of mitochondria along with the crosstalks with other cellular organelles, has led and will further lead toward the creation of better and more effective drugs. Moreover, the most modern approaches toward drug discovery and the introduction of artificial intelligence will allow scientists to exploit new opportunities.
Using an approach called structure-based rational drug design, researchers at University of Texas, Dallas, have developed a revolutionary molecule that kills a broad spectrum of hard-to-treat cancers, including triple-negative breast cancer (TNBC), one of the most dreaded forms of human tumor. While there are effective treatments available for patients with ER-positive breast cancer, there are few treatment options for patients with TNBC, which lacks receptors for estrogen, progesterone and EGFR2 receptors. TNBC generally affects women under 40 and has poorer outcomes than other types of breast cancer. In the current work, scientists tested a novel compound called ERX-41 for its effects against breast cancer cells, both those that contain estrogen receptors and those that do not. ERX-41 did not kill healthy cells, but it wiped out tumor cells regardless of whether the cancer cells had estrogen receptors. In fact, it killed the triple-negative breast cancer cells better than it killed the ER-positive cells.
The researchers discovered that ERX-41 binds to a cellular protein called lysosomal acid lipase A (LIPA). LIPA is found in a cell structure called the endoplasmic reticulum (ER), where cellular preoteins becomes properly folded. For a tumor cell to grow quickly, it has to produce a lot of proteins, and this creates stress on the endoplasmic reticulum. Cancer cells significantly overproduce LIPA, much more so than healthy cells. By binding to LIPA, ERX-41 jams the protein processing and generates the so-called ER-stress response (ERSR). The researchers fed the compound to mice with human forms of cancerous tumors, and the tumors got smaller. The molecule also proved effective at killing cancer cells in human tissue gathered from patients who had their tumors removed. They also found that ERX-41 is effective against other cancer types with elevated endoplasmic reticulum stress, including hard-to-treat pancreatic and ovarian cancers and glioblastoma, the most aggressive and lethal primary brain cancer.
The research team also tested the compound in healthy mice and observed no adverse effects. ERX-41 and related compounds have been protect by patenting since the beginning nad they have been licensed to the Dallas-based startup EtiraRX, a company co-founded in 2018 by some of the authors of this study. The company recently announced that it plans to begin clinical trials of ERX-41 as early as the first quarter of 2023.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Advised in this website
Guardado Rivas MO et al. PLoS One 2022; 17(6):e0269620.
Liu X, Viswanadhapalli S et al. Nature Cancer 2022 Jun 2.
Wen H et al. Int J Biol Sci. 2022 Apr 11; 18(7):2898-2913.
Martinez-Reyes I et al. Nature Rev Can. 2021; 21:669–680.
Dott. Gianfrancesco Cormaci
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