Lung cancer expert Triparna Sen delivered a seminar in the Cancer Biology Seminar Series at the University of Wisconsin Jan. 22. The seminars are hosted weekly by the McArdle Laboratory for Cancer Research at the Health Sciences Learning Center.
Sen’s lab at the Icahn School of Medicine at Mount Sinai Hospital focuses on lung cancer research broadly. During the seminar Wednesday, Sen spoke about three distinct topics, spanning specific cancer types to cancers that change what cells they are.
Sen started the seminar by speaking about the effects of oncogenes in adenocarcinoma, a cancer in the cells lining the lungs. Oncogenes are genes related to the development of cancer either through their mutation or inability to function.
Sen focused on genes that prevented ferroptosis, a process in which a cell dies through the accumulation of toxins in the cell. Cancer cells can inhibit ferroptosis by increasing the presence of proteins that prevent toxin accumulation.
Gene knockouts are the inactivation of genes typically through mutations. The mutations render the created proteins nonfunctional. Certain gene knockouts prevent treatments that induce ferroptosis in cancer cells from being effective.
In these cancer variants, Sen’s lab found that inhibiting SCD1 — a protein that maintains the balance of saturated to unsaturated fatty acids in cells — was able to decrease the size of tumors in mice for some time.
Sen then pivoted to small-cell lung cancers and her teams’ research on cancers with two gene knockouts that make them resistant to other treatments and the immune system. By knocking out an additional two genes, Sen’s lab saw improvement in the immune response to the tumors.
The last subject Sen spoke about was cancers which transformed cell types.
During treatment with tyrosine kinase inhibitors, a subset of adenocarcinomas transformed into small-cell cancers. After transformation, analyses conducted by Sen’s lab showed these cancers shared hallmarks of certain gene mutations but not at the expected level. This led Sen to suspect epigenetic inhibitions in the transformed cancers without mutations.
Epigenetics is the process in which gene transcription is modified by factors outside of what is in the genetic code. The genes silenced by mutations in some transformed cancers were epigenetically silenced in those without mutations.
The method of transformation between cell types is unclear. Sen theorized the deregulation of certain pathways allowed new cancer cells to develop into either the original or different but related cells. In this case, glandular epithelial cells — the cancerous cells in adenocarcinomas — differentiated into cancerous small cells.
Jazz Pharmaceuticals asked Sen’s lab to conduct trials with lurbinectedin, a drug designed to attack transformed small cell carcinomas. When paired with osimertinib, a TKI, tumors shrunk significantly and for an extended period compared to either drug on its own in human trials.
Following the conclusion of Sen’s seminar, the National Institute of Health suspended communications, research and grant meetings. Sen’s lab receives a portion of its funding through an R01 Chartered Study Section grant from the National Cancer Institute, an agency of the NIH.