How Clinical Trials Can Lead to AYA Brain Tumor Treatments

Transcript

• 00:05In general, a tumor grows
• 00:06when we have one of
• 00:07two types of mutations. Either
• 00:08mutation that's telling the cells
• 00:10to grow out of control
• 00:11or the opposite, where we've
• 00:12got a mutation that is
• 00:13tamped down the genes that
• 00:15tell it not to grow.
• 00:17And so with a brain
• 00:18tumor, with with any tumor,
• 00:19when we have these mutations,
• 00:20it's disrupting the normal flow
• 00:22of growth and apoptosis or
• 00:24or natural death.
• 00:26Normal cells, cancer cells are
• 00:28fascinating that every eight hours
• 00:29when they divide, there's billions
• 00:31of DNA that needs to
• 00:32be repaired.
• 00:34When they're replicated there'll be
• 00:35mistakes that are made
• 00:37and the DNA damage response
• 00:39pathways are responsible for fixing
• 00:41those errors. Now normal cells
• 00:42don't divide that often so
• 00:44they don't make a lot
• 00:44of errors, But cancer cells
• 00:46are rapidly dividing and rapidly
• 00:48growing, and such that there
• 00:49are many mistakes that occur,
• 00:51and the DNA damage response
• 00:52pathways help them survive,
• 00:55through those replication cycles.
• 00:58Often they have defects or
• 01:00they have
• 01:01dysfunctional ways that they run
• 01:03those pathways.
• 01:05And central to that is
• 01:06one protein called PARP
• 01:08that's implicated
• 01:09in brain tumor survival.
• 01:11If we can target those
• 01:12proteins that aren't supposed to
• 01:14be there, then we've got
• 01:15to target a therapy. And
• 01:16we can fight what we
• 01:17call the driver of the
• 01:18tumor and make it stop
• 01:19growing.
• 01:26In about two thousand fifteen,
• 01:27when our lab had just
• 01:28started at Yale, about three
• 01:30years into my faculty,
• 01:32we made a series of
• 01:33discoveries
• 01:34where we found that certain
• 01:36tumor associated mutations
• 01:37found in adults, but more
• 01:39often pediatric and what we
• 01:41call the,
• 01:42adolescent young adult population or
• 01:44the AYA population,
• 01:46we found that there was
• 01:47mutations specifically in those tumors
• 01:50that caused DNA repair defects.
• 01:53What was very interesting is
• 01:54that in my early faculty,
• 01:56I won a Cureshurt Young
• 01:58Investigator Award.
• 01:59And this was a three
• 02:00year award that really provided
• 02:03the infrastructure
• 02:04for us to make the
• 02:05discovery, which was the link
• 02:06between IDH mutations
• 02:08and DNA repair.
• 02:11We were able to treat
• 02:12cells that have the IDH
• 02:14mutation with a class of
• 02:15drugs that are FDA approved
• 02:16called PARP inhibitors.
• 02:18PARP inhibitors work against tumor
• 02:20cells that have this defect,
• 02:21and we realized that we
• 02:22could use the FDA approved
• 02:24PARP inhibitors and try them
• 02:25in young adult pediatric patients
• 02:28that have these IDH mutant
• 02:29gliomas.
• 02:30So you've got a very
• 02:31small population with very specific
• 02:33mutations
• 02:34that need to be studied
• 02:35on their own. As you
• 02:36can imagine, very difficult to
• 02:38get funding for this sort
• 02:39of trial. And that's when
• 02:41we went back to Curesearch
• 02:43and were able to take
• 02:44advantage of the Curesearch Catapult
• 02:45award. And this award allowed
• 02:47us to essentially take this
• 02:49bench discovery
• 02:50and move it directly into
• 02:52the bedside.
• 02:53The trial that doctor Bindra
• 02:54and I worked on has
• 02:55many components to it. And
• 02:56so it takes many different
• 02:58experts,
• 02:59and it takes a large
• 03:00amount of funding sources to
• 03:01make it all come together.
• 03:03We are always grateful to
• 03:05our donors, the foundations that
• 03:07support
• 03:08this really difficult work. And
• 03:10so we looked at other
• 03:11consortiums like the Pacific Neuro
• 03:13Oncology Consortium,
• 03:15who actually then allowed us
• 03:16to run our trial across
• 03:17a broader network of sites,
• 03:19and they also provided their
• 03:20own funding. And so working
• 03:22together with the Curessearch and
• 03:23the PNOC,
• 03:24group, we were able to
• 03:25do a national trial in
• 03:27a role of fairly large
• 03:28number of patients in a
• 03:29short period of time.
• 03:35I think this trial is
• 03:36helping us be more cognizant
• 03:38of specific mutations and unique,
• 03:41targets that we can look
• 03:43at in adolescent and young
• 03:44adult tumors.
• 03:45Priscilla was a really interesting
• 03:47and unique case.
• 03:49Her tumor
• 03:50was a high grade tumor,
• 03:51at the same time it
• 03:52carried a specific mutation that
• 03:54we thought that we could
• 03:55target. Obviously, I was dealing
• 03:57with this new diagnosis
• 03:58that came out of nowhere.
• 04:00It was an inoperable tumor.
• 04:02So from the beginning they
• 04:04told me we're gonna start
• 04:05radiation.
• 04:06I was,
• 04:07twenty three and living on
• 04:09my own,
• 04:10and where I needed to
• 04:12get radiation
• 04:13was two and a half
• 04:14hours away and then during
• 04:16radiation they said a few
• 04:17days after you finish radiation
• 04:19we're gonna start the chemo
• 04:20but then,
• 04:21I wasn't even finished with
• 04:22the first cycle
• 04:24when I had to go
• 04:24into the hospital
• 04:26and after after testing they
• 04:27saw the bad brain inflammation.
• 04:30And so thankfully,
• 04:32we reevaluated
• 04:34and I was I I
• 04:35was referred to you over
• 04:37here. Well, the initial,
• 04:39work out at Binger's lab
• 04:40informed the trial. The trial
• 04:42has given us confidence in
• 04:44treating patients with this particular
• 04:46class of drug,
• 04:48in this particular mutation.
• 04:49And so when we saw
• 04:50Priscilla's mutation, we had the
• 04:52confidence to go ahead and
• 04:54try this treatment course. Feeling
• 04:55more confident
• 04:56in the care I was
• 04:57receiving made a big difference
• 04:59because even though I was
• 05:00sick, even though I was
• 05:01not feeling well, as long
• 05:02as I felt like we
• 05:03were truly fighting the the
• 05:05disease,
• 05:06then I saw an end
• 05:08in InSite,
• 05:09and that helped that helped
• 05:10a lot. We've gotten control
• 05:12of Priscilla's tumor. She is
• 05:14still tumor free despite the
• 05:15fact that she's off medication
• 05:16and she's doing great. So
• 05:18even though we had treated
• 05:20fifty, sixty patients in this
• 05:21trial, we already saw evidence,
• 05:24early evidence of efficacy in
• 05:25response, which then allows us
• 05:27to treat patients with the
• 05:28same tumor. And that's what's
• 05:30the beauty of these small
• 05:31trials having a massive impact
• 05:33on pediatric cancer research.