UCLA Health Jonsson Comprehensive Cancer Center – The scientist designing a tailored attack on glioblastoma

“Being able to offer patients even a glimmer of hope is inspiring,” said Dr. Nathanson, a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and a member of the UCLA Health Jonsson Comprehensive Cancer Center.

In graduate school at UCLA, Dr. Nathanson encountered cancer research, where he was drawn to both the intellectual challenge and the opportunity to tackle complex problems for those who truly need it.

The importance of new therapies 

New therapies for glioblastoma are urgently needed. It is among the most lethal cancers, with only 5% of patients surviving five years after diagnosis. 

Despite decades of research, progress has been slow; more than 90% of drugs tested in clinical trials for glioblastoma have failed. 

Glioblastomas are highly heterogeneous, making single-pathway treatments insufficient. They also reside behind the blood-brain barrier, blocking many drugs from reaching the tumors.

Many therapies tested in glioblastoma were originally developed for cancers outside the central nervous system, such as lung or breast cancer. Glioblastomas are different in both location and functionality, and that mismatch has contributed significantly to the high failure rate.

A personalized approach 

Dr. Nathanson leads a translational brain tumor program that aims to better understand glioblastomas and exploit their differences to design more precise therapies.

He and his team map the metabolic features and signaling pathways that distinguish tumors from one another. Tumors can vary dramatically at the molecular and genetic level, helping explain why treatments that work for one patient may fail in another. 

They are working to understand how these variations drive the tumor, and how they can identify vulnerabilities that can be targeted therapeutically.

The protein epidermal growth factor receptor, or EGFR, is a molecular driver in many glioblastomas. EGFR alterations occur in more than half of glioblastomas, playing a central role in tumor growth, proliferation and metabolism.

Existing EGFR-targeting drugs were designed for cancers outside the brain. In glioblastoma, mutations occur in different receptor regions, altering drug interaction. Many therapies also cannot cross the blood-brain barrier, limiting their reach to brain tumors.

“We need an approach designed specifically for glioblastoma,” Dr. Nathanson noted

A drug built for glioblastoma

Rather than trying to adapt an existing therapy, Dr. Nathanson set out to engineer a new drug that could penetrate the brain and bind EGFR mutations without overwhelming toxicity.

He partnered with neuro-oncologist Timothy Cloughesy, MD, distinguished professor and director of the Neuro-Oncology Program and co-director of the UCLA Brain Tumor Center, and chemist Michael Jung, PhD, a UCLA distinguished professor of chemistry and biochemistry, who has helped develop FDA-approved cancer drugs. 

The collaboration combined tumor biology, clinical insight and medicinal chemistry to develop a drug to target glioblastoma. 

“You have to understand the mutation driving the tumor, but you also have to respect the unique environment of the brain,” Dr. Nathanson said.

Alongside Dr. Cloughesy’s clinical program, the team tested compounds in patient-derived glioblastoma models, identifying a candidate that could penetrate the brain and selectively target EGFR alterations.

The result was KTM-101, a purpose-built drug that’s engineered to penetrate the blood-brain barrier and selectively target glioblastoma mutations of EGFR. 

From bench to bedside

Phase I clinical trials for KTM-101 demonstrated that the drug is safe and well-tolerated, reaching therapeutically meaningful levels in the brain. Researchers observed early signs of efficacy in patients with late-stage glioblastoma, where benefits are rarely seen, giving the team confidence that the drug is hitting its target and making a difference.

The team hopes to move KTM-101 earlier in treatment, when tumors may be more vulnerable. 

Dr. Nathanson views KTM-101 as part of a larger effort to combat a disease known for adaptation. His laboratory is exploring additional strategies that anticipate how glioblastoma evolves, aiming to sustain tumor control over time. 

Dr. Nathanson said he and his team are building more than just a drug; they are creating a platform for designing therapies specifically for the biology of brain tumors. 

The goal is urgent: extend the lives of patients facing this diagnosis.

UCLA’s Brain Tumor Program helps enable the rapid translation of laboratory discoveries into clinical trials. Led by neurosurgeon Linda Liau, MD, PhD, and Dr. Cloughesy, the program brings together multidisciplinary specialists in a tightly integrated ecosystem.

“The hardest part is translating discoveries into something that truly reaches patients,” Dr. Nathanson said. “The collaborative infrastructure at UCLA makes that translation possible.”