A detailed look at a mysterious mutation present in many different cancer types has revealed new drug targets that, when hit with a combo of well-known compounds, led to tumor cell death and prolonged survival in mice. The results may eventually lead to new therapeutics that are effective across a broad swath of cancers.
The mutation in question is in the gene BAP1, and it comes with conflicting effects. An inherited BAP1 mutation virtually guarantees a person will develop cancer, but the tumors may be less invasive and easier for patients to survive. Conversely, if the cancer itself mutates to knock out BAP1, it can lead to a more aggressive disease.
“BAP1 mutations are relatively common across several aggressive cancers, but there are still limited targeted treatment options for these patients,” Bin Tean Teh, M.D., Ph.D., a clinician-scientist at Duke-NUS Medical School and National Cancer Center Singapore and the senior author of the new study, told Fierce Biotech. “That gap between biological importance and clinical translation was a key motivation for us.”
The new study, published today in Science Translational Medicine, took a close look at the proteins that BAP1 regulates. BAP1 is known as a deubiquitinase, a type of enzyme that helps protect other proteins from being broken down by the cell’s waste disposal system.
By characterizing BAP1’s activity, the scientists found that the protein plays a previously unrecognized role in a DNA repair pathway known as nucleotide excision repair. When two newfound partners of BAP1, called lysine-specific histone demethylase 1 (LSD1) and poly(ADP-ribose) polymerase 1 (PARP1), are inhibited in BAP1-deficient cancers, this form of DNA maintenance is disrupted and the cell dies.
“Our findings suggest that BAP1 contributes to maintaining genome integrity, in part by regulating proteins involved in DNA damage recognition,” Jing Han Hong, Ph.D., lead author of the study, told Fierce. Losing BAP1 may therefore destabilize the genome and ultimately lead to tumor progression, she said.
The researchers took tumors from patients and engrafted them onto mice, and then treated them with two compounds meant to block LSD1 and PARP1 at the same time. One of these is LSD1 inhibitor seclidemstat from Salarius Pharmaceuticals (now part of Decoy Therapeutics), while the other is AstraZeneca and Merck’s long-approved PARP inhibitor Lynparza.
In these mouse models, the combination therapy proved effective at shrinking tumors and improving survival in bile duct cancer, renal cell carcinoma, mesothelioma and uveal melanoma, the researchers reported.
The fact that both inhibitors have already been tested in humans should make it straightforward to test the combo in clinical trials, Michele Carbone, M.D., Ph.D., an oncologist at the University of Hawaiʻi Cancer Center who was not involved with the new study, told Fierce. Carbone led the 2011 discovery that BAP1, then a scarcely studied gene, is linked to cancer.
“At this stage, our work is preclinical, and we are working on furthering the research through collaborations with clinical and industry partners,” Teh said.
Carbone called BAP1 a “paradox” because of its seeming ability to both promote and slow cancer, depending on the circumstances. He has for decades studied families that have BAP1 mutations that predispose them to developing mesothelioma, a rare cancer that is typically caused by exposure to asbestos.
“There are only four tumor suppressor genes that, when they are mutated in the germline, they cause cancer in 100% of those who inherit the mutation,” Carbone explained. “And BAP1 is one of them.”
Despite this, mesothelioma in these families tends to be milder, he said, with patients surviving seven times longer than those who didn’t inherit a BAP1 mutation.
“These people don't die,” Carbone said. “Mesothelioma in a carrier of BAP1 mutation in the germline is a different disease.”
While Teh and Hong are attempting to target BAP1 to treat cancers with BAP1 mutations, Carbone endeavors to inhibit the protein in patients without mutations to emulate what he sees in the families he studies.
“During the course of their life, they get a lot of cancer, but they survive them,” Carbone said of the families. “I think that if we can figure it out, we can help a lot of patients by modulating BAP1 expression.”