CNS Anticancer Drug Discovery and Development: 2016 conference insights

Abstract

The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669-286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/ biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time-and cost-efficient clinical trials based on surrogate end points.

Cerebral microcirculation in glioblastoma: A major determinant of diagnosis, resection, and drug delivery

“…[71][72][73][74] Thus, inadequate drug delivery to the brain is a major limiting factor in the treatment of HGG. 9,75 Several different approaches are being tried to enhance drug delivery to the brain. 76 They include transient opening of the BBB via infusion of hyperosmotic mannitol, 77 focused ultrasound, 78,79 Trojan horse approach via endothelial transferrin receptors 74 and ultrashort pulsed laser.…”

“…Limiting treatment options, nearly all other approved and experimental drugs have shown no positive effects in glioma therapy. Molecular and genetic analyses have led to better disease stratification, but not to effective therapies 9,10 . Maximal resection of contrast‐enhancing tumor followed by radiation and chemotherapy according to the Stupp protocol (EBRT/TMZ followed by metronomic TMZ) until evidence of recurrence is the only approved first line of treatment for newly diagnosed GBM.…”

“…Molecular and genetic analyses have led to better disease stratification, but not to effective therapies. 9,10 Maximal resection of contrast-enhancing tumor followed by radiation and chemotherapy according to the Stupp protocol (EBRT/TMZ followed by metronomic TMZ) until evidence of recurrence is the only approved first line of treatment for newly diagnosed GBM. Indices of survival being directly proportional to the extent of resection (EOR), efforts are ongoing to maximize the surgeon's ability to identify the tumor margins during resection.…”

How far will the Voyager ® take us?

“…New therapies, especially new chemotherapy drugs, have been limited to brain penetrant alkylating agents (i.e., carmustine, lomustine, and temozolomide) since the 1970s. There are several reasons for this, which relate to drug delivery to infiltrative tumor cells behind the blood–brain barrier (BBB), drug residence time on tumor cell target, appropriateness of cellular target and the need to inhibit more than one cellular target, drug pharmacokinetics and drug safety [8,9].…”

Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas

“…Brain tumors are challenging to treat, largely due to their biological features including a high level of heterogeneity and complicated resistance mechanisms (1,2). Only a small percentage of drugs investigated through clinical trials become an established therapy, underscoring the importance of preclinical investigations where promising drug candidates can be studied, thereby increasing the chance for successful drug development.…”