Drug found to double survival time for glioblastoma patients
Mays Cancer Center Annual Report
By Steven Lee
A drug developed at The University of Texas at San Antonio has been shown to extend survival for patients with glioblastoma, the most common primary brain tumor in adults.
Results of a trial led by the university revealed that a unique investigational drug formulation called Rhenium Obisbemeda (186RNL) more than doubled median survival and progression-free time, compared with standard median survival and progression rates, and with no dose-limiting toxic effects.
“As a disease with a pattern of recurrence, resistance to chemotherapies and difficulty to treat, glioblastoma has needed durable treatments that can directly target the tumor while sparing healthy tissue,” said Andrew J. Brenner, MD, PhD, professor and chair of neuro-oncology research with Mays Cancer Center. “This trial provides hope, with a second phase under way and planned for completion by the end of this year.”
Brenner, who also is clinical investigator for the Institute for Drug Development at UT San Antonio and co-leader of its Experimental and Development Therapeutics Program, is lead author of the trial’s study, titled, “Convection Enhanced Delivery of Rhenium (186Re) Obisbemeda (186RNL) in Recurrent Glioma: a multicenter, single arm, phase 1 clinical trial.” It published in the journal Nature Communications.
Other authors also are with Mays Cancer Center, as well as UT Southwestern Medical Center of Dallas, Case Western Reserve University, University of Texas MD Anderson Cancer Center and trial sponsor Plus Therapeutics Inc., a clinical-stage pharmaceutical company receiving license to the trial technology to investigate the treatment of central nervous system cancers.
Brenner said that the median overall survival time for patients with glioblastoma after standard treatment fails with surgery, radiation and chemotherapy is only about eight months. More than 90% of patients have a recurrence of the disease at its original location.
Rhenium Obisbemeda enables very high levels of a specific activity of rhenium-186 (186Re), a beta-emitting radioisotope, to be delivered by tiny liposomes, referring to artificial vesicles or sacs having at least one lipid bilayer. The researchers used a custom molecule known as BMEDA to chelate or attach 186Re and transport it into the interior of a liposome where it is irreversibly trapped.
In this trial, known as the phase 1 ReSPECT-GBM trial, scientists set out to determine the maximum tolerated dose of the drug, as well as safety, overall response rate, disease progression-free survival and overall survival.
After failing one to three therapies, 21 patients who were enrolled in the study between March 5, 2015, and April 22, 2021, were treated with the drug administered directly to the tumors using neuronavigation and convection catheters.
The researchers observed a significant improvement in survival compared with historical controls, especially in patients with the highest absorbed doses, with a median survival and progression-free time of 17 months and six months, respectively, for doses greater than 100 gray (Gy), referring to units of radiation.
Importantly, they did not observe any dose-limiting toxic effects, with most adverse effects deemed unrelated to the study treatment.
“The combination of a novel nanoliposome radiotherapeutic delivered by convection-enhanced delivery, facilitated by neuronavigational tools, catheter design and imaging solutions, can successfully and safely provide high absorbed radiation doses to tumors with minimal toxicity and potential survival benefit,” Brenner concluded.
Researchers discover way to slow or block recurrence of glioblastoma
By Steven Lee
Researchers at The University of Texas at San Antonio have discovered a way to delay or even block recurrence of the deadliest brain cancer after radiation, bringing new hope
for survival.
Ironically, the scientists found that the customary treatment for glioblastoma, ionizing radiation, can also cause tumors to recur, by generating senescent or aged cells that secrete molecules that can spur growth of neighboring cancer cells.
But they discovered that a new class of experimental “senolytic” drugs, given after radiation, can kill those senescent cells while sparing normal ones, thereby stemming recurrence. A senolytic refers to a novel class of small molecules thought to selectively induce death of senescent cells.
“These findings lend credence to the ‘one-two punch’ approach to radiation therapy, where radiation or other agents are first used to induce senescence in a tumor, and then the senescent cells are removed by a senolytic,” said Sandeep Burma, PhD, professor and vice chair (research) of neurosurgery at UT San Antonio and Mays Cancer Center.
Burma and Bipasha Mukherjee, PhD, associate professor of neurosurgery at UT San Antonio, are lead authors of the study, “Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy,” published Feb. 19 in the journal EMBO Molecular Medicine. Other authors also are with the departments of neurology, biochemistry and structural biology, and medicine at UT San Antonio, as well as the University of Texas Southwestern Medical Center in Dallas, and the Mayo Clinic of Rochester, Minnesota.
A double-edged sword
Recurrence of glioblastoma, the most common primary brain tumor in adults, is a major clinical problem as it occurs quickly and can be even more aggressive. Accordingly, Burma’s lab has focused on understanding the forces driving recurrence and strategies to block the process.
Specifically, they are trying to understand whether senescence of cancer cells after radiation therapy – also called therapy-induced senescence, or TIS – might counterintuitively be driving recurrence.
Burma said that ionizing radiation, which is routinely and, in many cases, effectively used to treat cancer, is a double-edged sword since radiation also is a powerful carcinogen. For glioblastoma, radiation is still the most effective therapy. But radiation exposure also is the only known risk factor for its development, and could perhaps also drive recurrence.
When a tumor is radiated, a cancer cell can either die or remain alive but be permanently unable to divide further, a state called senescence, with both outcomes controlling tumor growth.
However, researchers in this study discovered that senescent glioblastoma cells secrete large amounts of growth factors and other molecules that can act on persisting cancer cells and encourage them to re-proliferate. What could be done about this problem?
End of senescence
Senolytic gets its name from the words “senescence” and “lytic,” or destroying.
The researchers found that senescent glioblastoma cells rely on an anti-apoptotic protein, or one that slows or prevents cell death known as cIAP2, for survival. They also found that targeting cIAP2 with a senolytic drug called birinapant in mouse tumor models after radiation could kill senescent cells while sparing normal cells.
They tested their approach in multiple mouse models of glioblastoma and found that while the drug was not effective on its own, it was very effective at delaying or even preventing recurrence if given as an “adjuvant” after radiotherapy.
“These pre-clinical results highlighting a novel senolytic approach for glioblastoma are very exciting from a clinical standpoint as they clearly indicate that significant improvement in patient survival may become possible by eliminating senescent cells arising after radiotherapy,” Burma concluded.
