AACR distinguished lecturer discusses cell cycle discoveries leading to targeted therapies

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Helen M. Piwnica-Worms, PhD
Helen M. Piwnica-Worms, PhD

Understanding the multiple pathways involved in regulating the cell cycle and how changes in cell cycle control mechanisms contribute to cancer has been vital to the development of targeted therapies for breast and other cancers. Helen M. Piwnica-Worms, PhD, was instrumental in defining the mechanisms of CDK1 activation and inactivation during the cell cycle. Her work at multiple institutions characterized CHK1, CDC25, and 14-5-5 protein interactions, providing the first link between cell cycle checkpoints and mitotic control mechanisms.

Dr. Piwnica-Worms, Senator A.M. Aiken Jr. Distinguished Chair and Professor of Experimental Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston, discussed her journey from basic research to translational trials during the 2021 AACR Distinguished Lectureship in Breast Cancer Research, Translation of Fundamental Cell Cycle Principles to Targeted Cancer Therapies, on Thursday.

Her task as a postdoctoral researcher was to unravel the transition from normal cell to cancer cell.

“Back in the day, if one was interested in studying cancer, one of the great ways was to use tumor virus DNA or RNA as your model system,” she said. “That’s because they are small as opposed to the linear human genome with three billion base pairs encoding 20,000 genes approximately. And we didn’t have all of the molecular technology available today to explore genes and tissues.”

One key step was the interaction of middle T antigen (MTag) and the pp60c-src protein kinase, but the mechanism was unknown. Dr. Piwnica-Worms showed that MTag transforms cellular SRC, changing its phosphorylation status to become an active protein tyrosine kinase. She also showed that the interaction between MTag and SRC phosphorylates downstream targets, leading to cellular transformation and proliferation.

Early work suggested that the phosphorylation of a single kinase, CDC2, is essential to drive mitosis, but those results were based on partially renatured CDC2. But when she added native CDC2 to cellular SRC, the pathway was not activated.

“Sometimes it is difficult to accept a negative result,” Dr. Piwnica-Worms said. “There can be a million reasons why that didn’t work. But SRC is a very promiscuous kinase and I had yet to find a substrate it would not phosphorylate. So, I believed this negative result.”

That failure suggested a new approach — looking at the cell cycle and cell cycle mutants. Cell cycle replication stress, typically DNA breaks, normally halts mitosis to allow for DNA repair. Two protein kinases, Wee1 and Mik1, redundantly halt the cell cycle in response to replication stress by phosphorylating CDC2, while CDC25s positively regulates entry into mitosis by dephosphorylating CDC2.

“Then we focused on how these regulators are regulated,” Dr. Piwnica-Worms said. “We were looking for some kind of checkpoint in the cell cycle pathway.”

A local presentation of her work to date sparked interest in 14-3-3 protein interactions, which led to the identification of multiple inhibitors targeting checkpoint proteins. The question was how to use them.

One approach was UCN-01, a potent inhibitor of Chk1 which causes activation of CDC2, resulting in premature entry into mitosis and cell death. Normal cells, containing p53, are not affected, but p53-deficient tumor cells are susceptible. A phase 1 clinical trial of 25 metastatic cancer patients treated with irinotecan and UCN-01 showed good results, with 60% of patients showing partial response or stable disease. But a phase 2 trial in triple negative breast cancer showed an overall response rate of just 4% and a clinical benefit rate of 12%.

“I realized I had an opportunity to use all we had learned to benefit breast cancer patients,” Dr. Piwnica-Worms said. “So, I relocated to MD Anderson where we could align our work with ongoing cancer trials. I look forward to continuing our work with the breast cancer community aimed at lifting the veil of breast cancer’s dark and chaotic nature.”

She is currently working with trials in triple negative breast cancer and germline deleterious BRCA mutations to identify and target mechanisms of chemotherapy resistance, drivers of breast cancer metastasis, mechanisms driving progression from in situ to progressive disease, and resistance to PARP inhibitors.