Knowing what we don’t know

By Susan Gammon, Ph.D.
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Sanford-Burnham scientists are awarded grants from the National Cancer Institute’s (NCI) Provocative Questions Initiative to find answers to scientific events that we know happen—but don’t know how they happen.

There are some scientific facts that we know, but don’t understand. Some of these facts are important but not obvious, and some have been studied but abandoned because we didn’t have ways to answer them. For example, scientists know that obesity and cancer are linked—but how? They know that some cancers peak in childhood, others in old age—but why?

The NCI Provocative Questions grants are aimed to support research that will define boundaries between the known and the unknown. The Initiative was established in 2012 and has awarded more than $22 million to 57 grant recipients nationwide. Questions are designed so that, if answered, they have the potential to substantially change the way scientists approach cancer research.

Matthew Petroski, Ph.D., assistant professor, Robert Rickert, Ph.D., professor, and director, Inflammatory Diseases Program, and Yanxin Pei, Ph.D., research assistant professor, all from Sanford-Burnham, were keen to participate in the Initiative. After reviewing a list of 20 provocative questions posed by the NCI, they selected topics related to cancer evolution—and were rewarded with grants that fund their projects.

Petroski and Rickert opted to collaborate and chose the topic of how treating tumors with targeted therapy can lead to drug resistance. Targeted therapy is a type of cancer therapy that interferes with specific molecules needed for tumor growth. Darwinian selection theory suggests that massive cell killing with targeted therapy might drive the emergence of drug-resistant tumors. Varying the selective pressure during treatment—such as changing drug doses or using drug combinations—may change the kinds of tumor cells that live and die during cancer. Petroski acknowledges that the goal of cancer therapy is to achieve the best outcome for the patient. But, in some cases, might it be preferable to live for some time with a tumor compared to a tumor that degenerates rapidly but will almost certainly develop drug resistance?

Using a new cancer drug called MLN4924, Petroski and Rickert will work to understand the way drug resistance develops to mono-targeted therapeutics. MLN4924 is currently in clinical trials for multiple myeloma and B-cell lymphoma. Ultimately, their work could change the way patients receive MLN4924 and other mono-targeted therapeutics if treatment-associated drug resistance found in the lab is also found in patients.

Pei has taken on the provocative question, “Which molecular events establish tumor dormancy after treatment and what leads to recurrence?” The question is aimed to solicit research that will advance understanding of why some tumors “go to sleep” and are undetectable after initial treatment but then “wake up” later, causing a cancer relapse.

Pei’s study will use a mouse model for brain cancer whose cancer genes can be turned “on” and “off.” Using the model, they can cause the tumor to grow, sleep, and relapse. They can identify the molecules contributing to each phase of the tumor and, finally, screen for molecules that promote death to sleeping tumors.

If successful, her studies will lead to new ways to target sleeping cancer cells. Eliminating these cells would greatly improve the long-term survival of patients with brain cancer, and possibly with other cancers known to relapse after initial treatment.

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Susan Gammon, Ph.D.
Susan Gammon, Ph.D.

Susan is an associate director of Communications at Sanford-Burnham.

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