A newly-identified compound might eventually help mesothelioma patients overcome resistance to chemotherapy.
Chemotherapy resistance is one of the main reasons that mesothelioma treatments fail.
But researchers at Duke University and the Massachusetts Institute of Technology have identified a compound that combats resistance to chemotherapy with cisplatin.
Cisplatin is one of the primary drugs in first-line chemotherapy for mesothelioma. If mesothelioma cells can be sensitized to it, patients may have better outcomes.
First-Line Treatment for Malignant Mesothelioma
Pleural mesothelioma is a cancer that grows on the lining around the lungs. Peritoneal mesothelioma starts on the lining of the abdomen. Both types of mesothelioma are caused by asbestos exposure.
Chemotherapy with cisplatin and pemetrexed (Alimta) is the treatment that doctors usually try first for mesothelioma. Cisplatin is a platinum-based drug used to treat several different cancers.
If there is no resistance to chemotherapy, cisplatin and Alimta can scramble the DNA inside cancer cells. The damaged cells can no longer replicate and grow out of control. Ideally, mesothelioma cells will start to die and the tumor will shrink.
FIrst-line chemotherapy may be followed by mesothelioma surgery to remove what is left of the tumor. If surgery is not an option and the tumor comes back, patients may have more chemotherapy. This is often where resistance to chemotherapy shows up.
Combating Mesothelioma’s Resistance to Chemotherapy
Mesothelioma cells are good at protecting themselves from chemotherapy. They not only have built-in repair mechanisms, but they can also develop mutations to prevent further cell damage.
The process is called mutagenic translesion synthesis (TLS). TLS can make resistance to chemotherapy even stronger the second time around.
But the Duke and MIT researchers say there may be a way around the problem. They found a compound that targets TLS. The team used the small molecule inhibitor (JH-RE-06) to successfully prevent resistance to chemotherapy in the lab.
“JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines,” they report.
They also tried the drug on live mice with human melanoma. When the mice received JH-RE-06 and cisplatin together, their resistance to chemotherapy went way down.
The researchers say the study could lead to a new class of “chemotherapy adjuvants” that inhibit TLS. Adjuvants are drugs given along with mesothelioma treatment to make it work better.
Every year, about 2,500 Americans receive a mesothelioma diagnosis. Due to the high level of resistance to chemotherapy, most do not live beyond 18 months.
Wojtaszek, J, et al, “A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy”, Cell, Volume 178, Issue 1, https://doi.org/10.1016/j.cell.2019.05.028