Targeting CNS Cancers with Precision Radiotherapeutics

Central nervous system (CNS) cancers remain among the most complex and difficult-to-treat malignancies. With limited FDA-approved therapies and often poor prognoses, patients with brain and spinal cord tumors face considerable challenges.

Glioblastoma — which accounts for nearly half of all primary malignant brain tumors and affects approximately 3.2 per 100,000 Americans (around 15,000 new cases) annually — is one of the most recognized examples of this unmet need.

Another, often underappreciated, form of CNS involvement occurs in leptomeningeal metastases — secondary tumors that originate outside the CNS but invade the cerebrospinal fluid that surrounds and cushions the brain and spinal cord. These are reported in 5% to 8% of cancer patients, and approximately 132,000 individuals are diagnosed in the US each year.

Radiation remains a foundational treatment approach; however, traditional methods often damage healthy tissue, thereby limiting the dose that can be safely delivered.

In this Xtalks Clinical Edge interview, Dr. Marc Hedrick, President and CEO of Plus Therapeutics, discusses how the company is exploring targeted radiotherapeutics for CNS cancers — with a focus on glioblastoma and leptomeningeal disease — using precision delivery techniques designed to enhance therapeutic selectivity and clinical feasibility.

Xtalks Clinical Edge™: Issue 5 — Targeting CNS Cancers with Precision Radiotherapeutics

Xtalks Clinical Edge™ is a magazine for clinical research professionals and all who want to be informed about the latest trends and happenings in clinical trials. This magazine immerses you in a world where industry leaders, patient advocates and top researchers converge to provide the most insightful perspectives on clinical trials.

From Pediatric Surgery to Radiotherapeutic Development

Dr. Hedrick began his career as a pediatric and vascular surgeon at the University of California, Los Angeles (UCLA), where he also led research at the Laboratory of Regenerative Bioengineering and Repair.

During a fellowship at the University of California, San Francisco (UCSF), he worked with a pioneering team developing in utero interventions for fetuses with life-threatening congenital conditions.

“You could diagnose it [devastating life-threatening complications] by ultrasound before, so you knew a disease tsunami was coming for these kids,” he said.

This early exposure to treating high-risk populations informed his transition from academia to biotechnology. Since then, Dr. Hedrick has been involved in developing treatments across pediatric and adult populations, particularly where existing options remain limited.

Addressing the Therapeutic Gap in CNS Cancers

Plus Therapeutics is focused on CNS malignancies, where therapeutic innovation has lagged. According to Dr. Hedrick, several tumor types within this category have not seen new FDA-approved therapies in over a decade.

Radiation remains a central approach to treating these tumors, but the ability to deliver it precisely is limited by the therapeutic index — the balance between effective tumor dose and damage to surrounding tissue.

“We’re talking about a 100-to-1, so not 1-to-1, not 3-to-1, but a 100-to-1 therapeutic index is possible, meaning for every one molecule of radiation you’re getting to say the bone marrow, you’re getting 100 to the brain cancer or the spinal cord cancer. Those are terrific odds, and we’ve proven that in at least two different kinds of cancer and likely a third here coming relatively soon,” said Dr. Hedrick.

The company’s strategy is to improve the therapeutic index by combining a radiotherapeutic agent with targeted delivery techniques that aim to concentrate radiation at the tumor site while minimizing exposure to critical organs.

Plus Therapeutics is employing two methods specifically designed for the CNS anatomy. For glioblastoma, the team uses convection-enhanced delivery (CED), which infuses therapy directly into brain tissue through implanted catheters. For cancers affecting the cerebrospinal fluid (CSF), like leptomeningeal metastases, an intrathecal port system — reminiscent of chemotherapy ports — allows for repeated, localized access to the fluid space without significant systemic exposure.

Leptomeningeal Cancer: A Rising Complication

One of the main areas of focus for Plus Therapeutics is leptomeningeal metastases, which arise when primary cancer cells spread to the CSF. This complication is being seen more often as patients with primary cancers like breast, lung and melanoma live longer due to improved therapies.

“So, arguably, there’s an epidemic of leptomeningeal metastases in the community because more and more people are living longer with breast cancer or lung cancer, melanoma, but those cells aren’t cured,” he said.

Dr. Hedrick estimated that leptomeningeal cancer likely affects between 250,000 and 400,000 individuals in the US each year, if one takes into account both those who are undiagnosed and diagnosed.

Despite its frequency, leptomeningeal metastases lacks FDA-approved treatments. Patients typically survive four to six weeks without treatment, and up to a few months with intervention. As Dr. Hedrick put it in a sobering observation, “Even though there’s nothing approved, doctors will throw the kitchen sink at many of these patients to try to extend their life.”

Plus Therapeutics is exploring the use of an intrathecal port system, similar to those used for chemotherapy, to deliver therapy directly into the CSF. This outpatient procedure aims to localize treatment to the affected area while avoiding systemic toxicity.