The method of using a previously unknown defect as a target has given scientists hope. A small number of people with recent rectal cancer went away after receiving experimental treatment.
It was a modest experiment conducted by doctors at Memorial Sloan Kettering Cancer Center in New York, where participants were given the drug dostarlimab for six months. Each of their cancers had disappeared by the end of their study.
Researcher at the University of Texas at Dallas, Dr. A new molecule developed by Jung-Mo Ahn has been discovered to kill a wide variety of hard-to-treat malignancies, including triple-negative breast cancer, without harming healthy cells.
It took advantage of a defect in cells that had previously been overlooked by other drugs.
The research was published in the journal Nature Cancer and was conducted in isolated cells from both human cancer tissue and human tumors grown in mice. There are only a few options for patients with triple negative breast cancer.
For more than a decade, Ahn, one of the study's co-authors and an associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics at UT Dallas, has been working on small compounds that target protein-protein interactions in cells. He had previously developed drug candidates for treatment-resistant breast cancer and prostate cancer.
In their current research, Ahn and colleagues investigated the effects of a new molecule he developed, ERX-41, on breast cancer cells with and without estrogen receptors (ERs).
Individuals with ER-positive breast cancer now have successful treatments, while patients with triple-negative breast cancer (TNBC) have only a few options. It does not have estrogen, progesterone or human epidermal growth factor 2 receptors. TNBC is a type of breast cancer that affects women under the age of 40 and has a worse prognosis than other types of breast cancer.
“The chemical ERX-41 did not destroy healthy cells, but killed tumor cells, regardless of whether they had estrogen receptors or not,” Ahn said. “In fact, it destroyed triple-negative breast cancer cells more effectively than ER-positive breast cancer cells.” We were surprised at that moment. We figured it was supposed to target something in TNBC cells other than estrogen receptors, but we didn't know what."
No adverse side effects were seen in healthy mice.
The researchers soon discovered that ERX-41 binds to a biological enzyme called lysosomal acid lipase A (LIPA). LIPA is located in the endoplasmic reticulum, a cell organelle that processes and folds proteins.
“A tumor cell must produce a large number of proteins to develop rapidly, and this puts stress on the endoplasmic reticulum,” Ahn said. “LIPA is significantly overproduced by cancer cells compared to healthy cells. ERX-41 binds to LIPA, preventing protein processing in the endoplasmic reticulum, causing it to swell and eventually die.”
The researchers studied the chemical in healthy mice and found no adverse effects.
"It took us several years to find out which proteins were affected by ERX-41," Ahn said. This was the hardest part. We got into a lot of deadlocks, but we didn't give up," he said.
May fight deadliest malignancy
The researchers then fed this substance to mice with malignant tumors similar to those found in humans, and the tumors shrank.
Cancer cells were also destroyed by the chemical in human tissue taken from people who had the tumor removed.
They discovered that ERX-41 was effective against a variety of tumors with high endoplasmic reticulum stress, such as difficult-to-treat pancreatic and ovarian malignancies, as well as glioblastoma, the most "aggressive and deadly primary brain tumor".
D., professor of urology and pharmacology at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. Ganesh Raj and professor of obstetrics and gynecology at UT Health San Antonio, Dr. Ratna Vadlamudi is their co-author at ERX.
The molecule is a former UTD research scientist at Ahn's Bio-Organic/Medicinal Chemistry Lab, Dr. It was also synthesized by Tae-Kyung Lee.
Ahn is the co-owner of ERX-41 and related substances licensed to Dallas-based EtiraRX, which was co-founded by Ahn, Raj and Vadlamudi in 2018. Showing that successful new drugs are on the way, ERX-41 will launch in the first quarter of 2023.
Summary: Triple negative breast cancer (TNBC) has a poor clinical prognosis due to the scarcity of actionable therapeutic targets. Lysosomal acid lipase A (LIPA) is identified as a suitable molecular target in TNBC, and a stereospecific small molecule (ERX-41) that binds LIPA is identified.
ERX-41 causes endoplasmic reticulum (ER) stress leading to cell death and this effect is on target as evidenced by the resistance conferred by certain LIPA mutations. We show that ERX-41 activity is dependent on ER location and not LIPA lipase function. LIPA binding to ERX-41 reduces the expression of several ER-local proteins involved in protein folding. This specific sensitivity has a wide treatment window with no adverse consequences in normal mammary epithelial cells or animals. Small, orally accessible compounds that target LIPA inhibit protein folding, induce ER stress and result in tumor cell death, according to our findings, which can be used to treat solid tumors such as breast, brain, pancreatic and ovarian cancers.