An answer for glioblastoma?

RES-529 targets TORC1 and TORC2 protein complexes in a dissociative manner to address deadliest brain cancer

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BUFFALO GROVE, Ill.—Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common and most aggressive type of primary brain tumor in adults. RestorGenex Corp., a specialty biopharmaceutical company focused on developing therapeutic products to treat ophthalmologic, oncologic and dermatologic diseases, thinks it may have an answer. RestorGenex presented scientific data on a potential treatment for GBM at the Keystone Symposia Series on PI 3-Kinase (PI3K) Signaling Pathways in Vancouver, British Columbia, in January.
“GBM is a disease with a very poor prognosis,” said Stephen M. Simes, CEO of RestorGenex. “Less than 10 percent of newly diagnosed patients survive five years. Current standard of care extends overall survival only by approximately 13 to 15 months, and thus there is a clear unmet medical need for novel treatments to treat brain cancer.”
GBM is challenging to treat because the cells within the tumor are very resistant to most types of treatments. As a result, doctors may draw upon a variety of treatments to try to slow tumor growth. In addition, these rapidly growing tumors tend to have a tentacle-like structure, so it can be difficult to fully remove the tumor through surgery.
Titled “Validation of RES-529, a novel TORC1/TORC2 allosteric dissociative PI3K inhibitor in glioblastoma multiforme,” the RestorGenex presentation showed how the proprietary first-in-class PI3K/Akt/mTOR pathway inhibitor is capable of dissociating both TORC1 and TORC2.
“The data presented help to understand the use of RES-529 and the validity of targeting the TORC1 and TORC2 protein complexes in a dissociative manner for GBM. This, and other work, supports the rationale for RestorGenex’s plans to advance RES-529 into clinical trials in GBM,” said Dr. David Sherris, chief scientific officer of RestorGenex.
Sherris explained that RES-529 is an “allosteric, dissociative, first-in-class inhibitor of the PI3K/Akt/mTOR pathway.” It inhibits both TORC1 and TORC2 and is mechanistically differentiated from other PI3K inhibitors currently in development, he said.
“Signaling components of the PI3K pathway are central regulators of cell proliferation, growth, differentiation, survival and angiogenesis,” Sherris added. “When the pathway is dysregulated, PI3K has shown direct involvement in the majority of tumor types. Activation of this pathway has been observed in approximately 45 percent of glioblastoma cases, making PI3K inhibition a validated target for therapeutic intervention in GBM.”
The poster presentation discussed in-vitro and in-vivo data from preclinical studies evaluating RES-529 in GBM, a disease often characterized by elevated expression of PI3K. In the first study, RES-529 demonstrated an ability to inhibit signal transducers of the PI3K pathway controlled by TORC1 and TORC2 in a variety of tumor cells, including cells that have lost tumor suppressor PTEN.
A second study compared RES-529 with two catalytic inhibitors of the PI3K pathway currently in the clinic: a combination PI3K/mTOR agent and a combination PI3K/Akt agent. RES-529 showed a twentyfold to more than hundredfold increase in activity above the other inhibitors and demonstrated the ability to inhibit tumor cell survival up to two orders of magnitude over that of a rapamycin analog PI3K inhibitor in a tumor cell model known to show resistance to TORC1 inhibition.
A third study demonstrated that RES-529 penetrates the blood-brain barrier. This was supported by efficacy data of RES-529 in an orthotopic GBM xenograft model where RES-529 showed an improvement in survival vs. control, similar to radiation treatment. When utilized in combination with radiation, RES-529 showed synergy extending survival above that of either RES-529 or radiation alone.
Sherris concluded, “The data both as monotherapy and in combination therapy with radiation suggest that RES-529 should be evaluated in glioblastoma where standard of care has at best resulted in approximate survival of 12 months—fewer than 25 percent of patients survive two years, and fewer than 10 percent of patients survive five years.”
While it accounts for 52 percent of all primary brain tumor cases and 20 percent of all intracranial tumors, GBM occurs in only two or three cases per 100,000 people in Europe and North America. About 10,000 new cases of GBM are diagnosed in the United States each year—about 3.2 out of every 100,000 people. It is more common in older individuals, and more likely to affect men than women.

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