Glioblastoma: Alissa Thomas, M.D. & Delphine Quenet, Ph.D.
Glioblastoma is rare among cancers— Vermont’s registry shows only 30 cases of it annually (if it sounds familiar, that’s because it made news as the cause of death for senators
Ted Kennedy and John McCain). Despite its relatively low numbers, it has piqued the interest of researchers, partly because of its aggressiveness.
“Glioblastoma is a very invasive cancer, so you can never get a clean surgery with nice margins,” says Alissa Thomas, M.D. “It has tentacles that grow deep into portions of the brain, so you can’t treat it surgically.
It’s a cancer that tends to acquire a lot of different mutations, so it develops resistances to radiation and chemotherapy relatively quickly. And it grows fast, so most of the time patients show up with a couple weeks’ worth of symptoms at
most; the survival average is somewhere between one and two years.” Standard treatment combines surgery, radiation, and chemotherapy with temozolomide (Temodar®), but recurrence is largely anticipated. Because there is no cure and no effective
salvage therapy for glioblastoma, Thomas, a neurologist and neuro-oncologist, and Delphine Quenet, Ph.D., a basic science researcher and assistant professor in the department of biochemistry, are exploring whether a specific Poly (ADP-ribose) polymerase
(PARP) inhibitor could serve as an adjuvant to standard chemotherapy. They recognize the likelihood is slim that every patient would benefit from it, but hope to find those who will. To be able to offer such personalized therapy, says Quenet, is their
“dream goal.” The two acknowledge that theirs is not the standard approach to research, this quest for a one size-fits-some therapy.
“One of our frustrations in clinical trials for glioblastoma is that once you get to a big
enough clinical trial, most treatments fail. They fail because we set this benchmark that X percent of patients have to respond for this to be a successful trial. But with a lot of these trials, five percent of patients respond and that’s not good
enough to get the drug approved or make this the standard of care. Figuring out who those five percent are so that these patients do this trial and not a different one—that would have a huge impact,” says Thomas.
lab has been focused on the effect of PARP inhibitors on the metabolism and biology of glioblastoma cell lines, specifically PTEN, which is an enzyme that acts as a tumor suppressor and is often mutated or deleted in patients.
like to know if patients who are mutated for this tumor suppressor benefit more from the PARP inhibition or not, due to a concept called synthetic lethality, which has been developed these last 20 years in the PARP field,” she says. In essence,
synthetic lethality occurs when two genes with mutations are expressed simultaneously, leading to cell death. A familiar example is BRCA-related cancers, where PARP inhibi tors have enhanced the benefits of radiotherapy and chemotherapy. Quenet and Thomas
are hopeful that PTEN—which, like BRCA, is involved in double-strand break repairs— will similarly respond to a PARP inhibitor. Working with established cell lines from as far back as the 1960s, coupled with fresh samples donated by UVM Medical
Center patients that must be examined in real time, before cell death begins, Quenet’s lab uses biochemical, molecular, and immunohistochemical approaches to understand how proteins are expressed in the cells. When there are several, they look at
the subtypes to find any that might be more sensitive to therapy.
“If we see that one of Delphine’s cell lines is responding really well to treatment she’s doing in the lab, we can also look and see if this was a patient who
did particularly well or not well with the kinds of treatments we have available now. It gives us some real-life correlation,” says Thomas. The current treatment, temozolomide, works by attaching a methyl group to the backbone of DNA, which keeps
the DNA from crosslinking and replicating itself. Conversely, having a good DNA repair mechanism generally interferes with a patient’s ability to respond well to the chemotherapy. PARP is a DNA repair pathway that Quenet and Thomas think may be
influencing sensitivity to the chemotherapy.
“Patients often relapse, and one potential reason is because some cells are more resistant to the current treatment. Maybe they will be more sensitive to PARP inhibitor and that’s what
we need to address,” says Quenet. The two have also been building a small tissue bank they hope will allow them to undertake different kinds of research in the future, ideally with enough fresh tissue for them to follow their own cell lines. They
note the tremendous support they’ve had from patients in allowing use of tumor samples. The pair has been inspired by the desire of patients to play a role in advancing treatment for this disease. With initial support from the UVM Cancer Center
through an American Cancer Society Institutional Research Grant, their team has further evolved and is even more fully transdisciplinary; it now includes pathologist John Dewitt, M.D., Ph.D., and neuroscientist James Stafford, Ph.D. Neuroscientist Diane
Jaworski, Ph.D, has mentored Quenet and Thomas as they’ve applied for studies and grants—even helping Quenet by blinding her first samples.
“We’ve started to have a stronger minigroup around not only glioblastoma,but
brain tumors, and that’s good for everybody,” says Quenet.