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Two new papers, published simultaneously in Nature Communications and led by researchers at McGill University, offer the promise that a drug currently used to treat estrogen-positive bad cancer could be effective in treating two types of cancer. different cancer, one rare and the other common.
The breakthrough at the origin of this research took place in 2014 when Dr. William Foulkes, a James McGill Professor in the Departments of Medicine, Oncology and Human Genetics of the Faculty of Medicine at McGill University. McGill, has shown that small-cell carcinoma hypercalcemic (SCCOHT), a rare but very deadly cancer that mainly affects younger women, is caused by mutations in the SMARCA4 gene.
The challenge was to find a way to exploit this genetic deficit to better treat these patients. Dr. Sidong Huang, an badistant professor in the Department of Biochemistry at McGill's Faculty of Medicine and lead author of both papers, took up the challenge. After many years of training in functional genomics, Dr. Huang joined McGill to work on important issues in oncology. "Working on something like SCCOHT seemed like an obvious choice because it's a single genetic disease caused by the loss of a single gene, SMARCA4," says Dr. Huang, also a member of the Center. Goodman Cancer Research Group.
Dr. Huang and Dr. Foulkes then collaborated with Professor Janusz Rak, Associate Professor at the Research Institute of the McGill University Health Center (RI-MUHC), Dr. Barbara Vanderhyden of the Research Institute of the # 39; Ottawa Hospital and Dr. Sriram Venneti at the University of Michigan. Through their work, Dr. Huang and his PhD student, Yibo Xue, the first author of the journal, were able to identify that the targeting of 4/6 cyclin-dependent kinases (CDK4 / 6) exposed a vulnerability to SMARCA4-deficient cancers.
"What is clinically interesting in this work is that CDK4 / 6 inhibitors have been used for years, so they are well known and their safety profile is established," notes Dr. Foulkes. who also runs the Lady Davis Cancer Genetics Lab. Institute of the Jewish General Hospital and researcher at the RI-MUHC.
"In the case of SCCOHT, in particular, it is encouraging to find existing drugs that could prove effective because it is so rare a cancer that it is unlikely that it is the subject of a specific development, "adds Dr. Huang. "In addition, patients may also benefit from anti-tumor immunity elicited by CDK4 / 6 inhibitors, as has been recently shown in other cancers, in addition to direct inhibition. of the tumor by these drugs ".
Although much more widespread than SCCOHT, non-small cell lung cancer (NSCLC) can be very difficult to heal. "We extended the work of SCCOHT to NSCLC because we realized that about 10% of these common tumors also lacked SMARCA4," Xue explains.
It has been proven both in vitro on human cancer cells and in vivo on animal models that CDK inhibitors are effective in suppressing SMARCA4 deficient tumors.
"The fact that these drugs worked so well was a little surprising," says Dr. Foulkes. "It may work because the targeted protein is at extremely low levels in the tumor – just enough to keep the tumor alive, but remains susceptible to blockage."
"This contrasts with the initial application of this clbad of drugs to treat bad cancers that often express high levels of the same protein," Dr. Huang adds. "Thus, our results could potentially expand the applications of these drugs."
The precise mechanism by which these particular inhibitors act in the various cancers remains to be determined definitively. But, says Dr. Foulkes, it's an academic question. as long as the drugs prove effective, the clinical impact is undeniable.
"The next step is to check the effectiveness of these drugs in patients with SCCOHT or SMARTN4 deficient NSCLC and to identify other drug targets in these cancers, to inhibit in combination with inhibitors of CDK4 / 6, in order to overcome a possible resistance, "said Dr. Huang.
"The dream would be to cure these cancers, but any reference to an answer would be a positive step forward, especially because current treatments for women with SCCOHT have limited effectiveness," Dr. Foulkes concludes.
This article has been republished from documents provided by McGill University. Note: Content may have changed for length and content. For more information, please contact the cited source.
References:
Xue et al. 2019. CDK4 / 6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nature Communications. doi: 10.1038 / s41467-018-06958-9.
Xue et al. 2019. The loss of SMARCA4 is synthetic, fatal, with inhibition of CDK4 / 6 in non-small cell lung cancer. Nature Communications. doi: 10.1038 / s41467-019-08380-1.
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