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Drug combo therapy in mice blocks drug resistance, halts tumor growth

May lead to better treatments for deadliest form of lung cancer

by Tamara BhandariAugust 31, 2022

Simone Hausmann and Pawel Mazur

An experimental combination of two drugs halts the progression of small cell lung cancer, the deadliest form of lung cancer, according to a study in mice from researchers at Washington University School of Medicine in St. Louis, Grenoble Alpes University in Grenoble, France, and The University of Texas MD Anderson Cancer Center in Houston.

One of the drugs, cyclophosphamide, is an outdated chemotherapy drug once used to treat small cell lung cancer. It was displaced in favor of platinum-based drugs in the 1980s. Both kinds of drugs work at first but falter after a few months as the cancer develops resistance. Platinum-based drugs became the standard of care mainly because they cause lesser side effects, but they have not substantially improved prognosis. Today, the typical patient survives less than a year and a half after diagnosis.

In this study, however, researchers showed that small cell lung cancer cells resist cyclophosphamide by activating a specific repair process, and demonstrated that throwing a wrench into the repair process makes the drug much more effective, at least in mice. The findings, available online in Cancer Discovery, suggest a pathway to better therapies for one of the least treatable forms of cancer.

“Small cell lung cancer has one treatment option — platinum-based chemotherapy — and that adds maybe two to six months of life,” said co-senior author Nima Mosammaparast, MD, PhD, an associate professor of pathology & immunology and of medicine at Washington University, and a researcher at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “The problem is that these tumors respond to treatment initially, but then they come back. This has not changed for 30 years. These tumors are just massively resistant to just about everything. So what this study shows is that we can actually combine a new target with an old drug to reduce resistance and potentially make the treatment much better and give these patients a much better chance.”

The study came together fortuitously. Co-senior author Nicolas Reynoird, PhD, a professor at Grenoble Alpes University, studies how internal signaling within cells – and deregulation of such signaling – can lead to cancer progression and drug resistance. A few years ago, his team discovered that a protein called RNF113A may play a role in small cell lung cancer, but the researchers could not determine what the protein does. Meanwhile, Mosammaparast was studying how cells repair injured DNA. In 2017, he published a paper in the journal Nature describing how cancer cells repair a kind of DNA damage known as alkylation damage, the kind caused by cyclophosphamide. The paper noted that RNF113A plays a role in the process. Reynoird essentially cold-called Mosammaparast, and the two teamed up — along with co-senior author Pawel K. Mazur, PhD, an associate professor of experimental radiation oncology at MD Anderson and a longstanding collaborator of Reynoird’s — to investigate how small cell lung cancer cells resist alkylation damage, and whether it’s possible to magnify the effects of alkylating chemotherapy drugs such as cyclophosphamide by interfering with that resistance.

The team discovered that RNF113A is regulated by a protein called SMYD3 that is highly expressed in small cell lung cancer and some other cancers. High levels of SMYD3 are associated with more invasive disease, increased resistance to alkylating chemotherapy and worse prognosis. Healthy lung tissue has very little SMYD3, which led the researchers to think that knocking it down might target cancerous cells while sparing healthy ones.

So they tried it. The researchers created mouse models of human disease by grafting cancerous cells from two people with small cell lung cancer onto separate groups of mice. One set of cells came from a patient who had not yet been treated, so the cells had not had a chance to develop resistance. The other came from a patient who had been treated with and become resistant to standard platinum-based therapy.

All of the mice grew tumors. When the tumors were big enough, the researchers treated the mice with an inhibitor of SMYD3, cyclophosphamide, both or an inactive solution. Inhibiting SMYD3 alone modestly slowed down the growth of the tumors. Cyclophosphamide initially halted the growth of tumors from both patients, but the tumors started to grow again after about two weeks, indicating that they had developed resistance. However, the combination of the two drugs stopped the tumors in their tracks. They did not restart growing for the duration of the experiment.

“We’re talking to a number of other groups about starting a phase 1 clinical trial as soon as possible,” Mosammaparast said. “One of the challenges we will face is convincing doctors to go back to an old drug. But the nice thing about this strategy is that it may work where current therapies have failed. This treatment worked just as well against the tumor from the patient who had already relapsed on platinum-based therapy as it did against the untreated patient. People with small cell lung cancer are in desperate need of better treatments, and I’m very excited about the possibilities here.”

Lukinović V, Tsao N, Hausmann SC, Roth GS, Ahmad T, Oyeniran C, Brickner JR, Casanova AG, Chuffart F, Benitez AM, Vayr J, Rodell R, Tardif M, Jansen PWTC, Couté Y, Vermeulen M, Hainaut P, Mazur PK, Mosammaparast N, Reynoird N. SMYD3 impedes small cell lung cancer sensitivity to alkylation damage through RNF113A methylation-phosphorylation crosstalk. Cancer Discovery. Aug. 9, 2022. DOI: 10.1158/2159-8290.CD-21-0205

This study was supported by the French National Research Agency (ANR), grant number ANR-16-CE11-0018; the French National Cancer Institute (INCa), grant number PLBIO19-021; the Ligue contre le cancer (comité Savoie); Agir Pour les Maladies Chroniques; the Fondation ARC, grant number PJA 20181207702; the U.S. National Institutes of Health (NIH), grant numbers P01 CA092584, R01 CA193318, R01 CA227001, R01CA236949, R01CA236118 and K99CA255936; the American Cancer Society, grant number RSG-18-156-01-DMC, the Siteman Investment Program; the American Association for Cancer Research, the Neuroendocrine Tumor Research Foundation; the U.S. Department of Defense’s Peer Reviewed Cancer Research Program, award number CA181486; The University of Texas NIH SPORE in Lung Cancer Career Enhancement Grant, number P50CA070907; the Andrew Sabin Family Foundation; the Cancer Prevention and Research Institute of Texas, grant number RR160078; the Vermeulen lab is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society (KWF); proteomic experiments were partly supported by ProFI, grant number ANR-10-INBS-08-01; the German Research Foundation (Deutsche Forschungsgemeinschaft), fellowship number HA8434/1-1; and the French Foundation for Medical Research (FRM), fellowship number SPF201809006930.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% in the last five years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,790 faculty physicians practicing at over 60 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

Tamara covers pathology, immunology, medical microbiology, cell biology, neurology, and radiology. She holds a bachelor's degree in molecular biophysics and biochemistry and in sociology from Yale University, a master's in public health/infectious diseases from the University of California, Berkeley, and a PhD in infectious disease immunology from the University of California, San Diego. Tamara worked in laboratories for about a decade before switching to science journalism. She joined Medical Public Affairs in 2016.