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ID1 inhibition may improve efficacy of glioblastoma treatment
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Investigators from St. Michael’s Hospital and The Hospital for Sick Children in Toronto have determined that the transcriptional regulatory protein ID1 appears to maintain cancer stem cells in glioblastoma.
Results from studies conducted in mice — which laid the groundwork for a trial in humans — suggest ID1 inhibition could lead to better treatment efficacy.
“The field has postulated for years that cancer stem cells are a small population within the tumor, but [that they are] critical because they mediate treatment resistance and cancer resistance,” Sunit Das, MD, PhD, researcher at St. Michael’s Keenan Research Centre for Biomedical Science and The Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children, said in a press release. “We have now found proof of that speculation.”
HemOnc Today spoke with Das about the implications of this discovery, how it may improve treatment and the next steps in research.
Question: Can you describe the rationale for this research ?
Answer: I often see glioblastoma occur among young, otherwise healthy people. We treat this cancer aggressively, but the outcomes are unsatisfying. There is a great need for us to understand the biology of the disease and develop new treatments. These patients often present with a large mass on MRI. It seems we are able to achieve radiographic remission with current therapies, yet every patient experiences disease recurrence and death. This discrepancy suggests there must be residual cell populations that persist below the threshold of what we can see clinically, and that these tumor cells are responsible for recurrence. We tried to model what those tumor cell populations might be and find better ways to target them.
Q: How did you conduct the study?
A: Using tissue obtained from patients in the operating room, we developed tumors in immunocompromised mice and treated them with chemotherapy and radiation, just as we would a person. When we completed those treatments, we harvested the cells that survived those therapies in mice that we think would be analogous to the cells that survive therapies in our patients. We studied those cells to determine if they had a different identity from what we see when we evaluate the tumor as a whole.
Q: Can you elaborate on your findings?
A: We found markers that were specific to a small subpopulation of surviving cells. Many of those markers were similar to neural stem cells. We wanted to understand what allowed those cells to persist despite these otherwise effective therapies. We identified a role for ID1, which is important in normal stem cell biology because it plays a critical role keeping stem cells from maturing. ID1 does not bind directly to DNA; rather, it binds to and acts as a sequester transcription factor that would cause cell differentiation if it were able to bind to the DNA. In glioblastoma, we found something similar. ID1 allowed these cells to remain in a stem cell-like state. It also mediated the processes that allowed these cells to survive DNA damage secondary to radiation and chemotherapy. When we looked at patients, we found something very similar to what we observed in our animal model.
We took our research a step further and hypothesized that this gene and its product could be critical for maintaining the stem cell-like phenotype in these cells, allowing them to survive therapy and drive tumor recurrence. If this were the case, we hypothesized that inhibiting the gene would make chemotherapy and radiation more effective. We did this in two ways. First, we genetically knocked out ID1 in our tumor cells using CRISPR/Cas9. We found that genetic knockout of ID1 radically impaired the ability of these cells to create new tumors. Second, we determined that pimozide — a drug used as an antipsychotic agent — results in degradation of ID1. Treatment with this drug enhanced the efficacy of chemotherapy and radiation, and it extended survival in our mouse models.
Q: What is next for research?
A: Our findings are encouraging because the agent crosses the blood-brain barrier, but it is not quite clear that it would achieve high enough drug levels in the brain to do what it needs to do. We plan to study this in future research. The goal for all of us is to try to translate what we see in the lab to the clinic. We have built a team of collaborators throughout North America to consider strategies for how to do so and what approach we need to take. We plan to answer some key questions before moving this work to patients. We are working to start a phase 0 clinical trial to determine whether this agent can get where we need it to get to and inhibit the intended target. – by Jennifer Southall
Reference:
Sachdeva R, et al. Cancer Res. 2019;doi:10.1158/0008-5472.CAN-18-1357.
For more information:
Sunit Das, MD, PhD, can be reached at St. Michael’s Hospital, 30 Bond St., Toronto, ON M5B 1W8; email: sunit.das@utoronto.ca.
Disclosure: Das reports no relevant financial disclosures.