Meeting News

CURE scholar reflects on lessons learned in early-phase drug development

Adjei_Alex_80x106
Alex Adjei

In his presentation as a Continuing Umbrella of Research Experiences, or CURE, Distinguished Scholar, Alex Adjei, MD, PhD, professor of oncology and pharmacology at Mayo College in Rochester, Minnesota, discussed the many lessons he has learned in his 20-year career developing cancer treatments.

The CURE program is part of the NCI’s Center to Reduce Cancer Health Disparities. It is designed to provide opportunities in medicine and science to young people in underserved populations.

“The CURE Distinguished Scholar seminar series recognizes former CURE scholars who are making significant and substantial contributions in cancer or cancer health disparities research and also in workforce diversity,” Mary Ann S. Van Duyn, PhD, MPH, associate deputy director for integration at Center to Reduce Cancer Health Disparities, said in the presentation. “Dr. Adjei received one of our very first CURE awards back in 1997, when he was just starting as a lung cancer specialist and when patients with the disease had a very dismal prognosis. His research ... has focused on experimental therapeutics and clinical drug development, and this research has helped to contribute to progress in these areas for a number of cancers.”

Earlier efforts

Adjei discussed the phase 1 and phase 2 trials he conducted of farnesyl transferase inhibitors (FTIs) in non-small cell lung cancer. The phase 1 trial demonstrated that the FTI SCH66336 and cisplatin provided in vivo blockade of protein farnesylation.

"When I first started, the approach to targeting KRAS was focused on trying to prevent RAS translocation to the cell membrane,” Adjei said. “RAS is a small hydrophilic protein, and once it synthesizes, there’s post-translational modification, where a 15-carbon chain is added. After several iterations, the cell membrane is uncoated.”

He said after 12 iterations, the carbon chain makes RAS more lipophilic, enabling it to attach to the cell membrane from where it signals.

“The thinking then was that if you could prevent RAS from translocating to the cell membrane, the cytoplasm is not able to signal, so you will get RAS effect,” he said. “It turns out this process, called farnesylation, had a rate-limiting step, the first step, which was catalyzed by the enzyme farnesyltransferase.”

After a successful phase 1 study, Adjei and his colleagues initiated a phase 2 study on this class of drugs.

“Patients were lined up to get this drug, because we thought it was going to cure lung cancer,” he said. “All my initial studies were with a different drug, a compound from Schering-Plough, and it was getting too difficult to continue the work with the Schering compounds. We did a phase 2 study (with a different compound) and we carried that biomarker to the phase 2. And to put it simply, it didn’t work.”

Adjei’s group conducted several subsequent studies on MEK inhibitors and other agents, and eventually arrived at the work they are currently conducting.

Oncolytic viruses

Adjei’s group first considered the use of oncolytic viruses when contemplating some patients’ lack of response to immune checkpoint inhibitors.

“In spite of all this activity, how much do we shrink tumors? Apart from Hodgkin [lymphoma], we don’t have any tumor where you get 50% shrinkage when you use a checkpoint inhibitor,” he said. “What this means is, in spite of all the hype, the majority of patients actually don’t derive a lot of benefit. Why is this?”

He said one possibility is that the small minority of tumors that respond are inflamed; they could have mutations, DNA damage and more. For these tumors, an anti-PD-1 or anti-PD-L1 inhibitor would be effective.

Clinic researchers also began to explore the possibilities of oncolytic viruses in these tumors. They are currently using the vesicular stomatitis virus, a blunt-shaped RNA virus pathogenic to pigs, horses and cattle.

“This is naturally transmitted by certain flies, and they aren’t really seen as pathogenic for humans,” he said. “When humans are exposed to this virus, they get a mild flu, and it’s transient.”

Adjei said promising studies have been conducted in which an oncolytic virus, the coxsackievirus (CVA21, CAVATAK), combined with pembrolizumab (Keytruda, Merck).

“This is a one-time infusion of the virus and then continue with the pembrolizumab,” he said.

These studies have shown that the combination was well-tolerated and showed promising signs of activity. It also yielded substantial increases in PD-L1 tumor levels.

“This is exciting,” Adjei said. “With the advent of immunotherapy, we have been working toward using oncolytic viruses to enhance the efficacy of these checkpoint inhibitors.” – by Jennifer Byrne

Disclosures: HemOnc Today could not confirm Adjei’s relevant financial disclosure at the time of publication.

Adjei_Alex_80x106
Alex Adjei

In his presentation as a Continuing Umbrella of Research Experiences, or CURE, Distinguished Scholar, Alex Adjei, MD, PhD, professor of oncology and pharmacology at Mayo College in Rochester, Minnesota, discussed the many lessons he has learned in his 20-year career developing cancer treatments.

The CURE program is part of the NCI’s Center to Reduce Cancer Health Disparities. It is designed to provide opportunities in medicine and science to young people in underserved populations.

“The CURE Distinguished Scholar seminar series recognizes former CURE scholars who are making significant and substantial contributions in cancer or cancer health disparities research and also in workforce diversity,” Mary Ann S. Van Duyn, PhD, MPH, associate deputy director for integration at Center to Reduce Cancer Health Disparities, said in the presentation. “Dr. Adjei received one of our very first CURE awards back in 1997, when he was just starting as a lung cancer specialist and when patients with the disease had a very dismal prognosis. His research ... has focused on experimental therapeutics and clinical drug development, and this research has helped to contribute to progress in these areas for a number of cancers.”

Earlier efforts

Adjei discussed the phase 1 and phase 2 trials he conducted of farnesyl transferase inhibitors (FTIs) in non-small cell lung cancer. The phase 1 trial demonstrated that the FTI SCH66336 and cisplatin provided in vivo blockade of protein farnesylation.

"When I first started, the approach to targeting KRAS was focused on trying to prevent RAS translocation to the cell membrane,” Adjei said. “RAS is a small hydrophilic protein, and once it synthesizes, there’s post-translational modification, where a 15-carbon chain is added. After several iterations, the cell membrane is uncoated.”

He said after 12 iterations, the carbon chain makes RAS more lipophilic, enabling it to attach to the cell membrane from where it signals.

“The thinking then was that if you could prevent RAS from translocating to the cell membrane, the cytoplasm is not able to signal, so you will get RAS effect,” he said. “It turns out this process, called farnesylation, had a rate-limiting step, the first step, which was catalyzed by the enzyme farnesyltransferase.”

After a successful phase 1 study, Adjei and his colleagues initiated a phase 2 study on this class of drugs.

“Patients were lined up to get this drug, because we thought it was going to cure lung cancer,” he said. “All my initial studies were with a different drug, a compound from Schering-Plough, and it was getting too difficult to continue the work with the Schering compounds. We did a phase 2 study (with a different compound) and we carried that biomarker to the phase 2. And to put it simply, it didn’t work.”

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Adjei’s group conducted several subsequent studies on MEK inhibitors and other agents, and eventually arrived at the work they are currently conducting.

Oncolytic viruses

Adjei’s group first considered the use of oncolytic viruses when contemplating some patients’ lack of response to immune checkpoint inhibitors.

“In spite of all this activity, how much do we shrink tumors? Apart from Hodgkin [lymphoma], we don’t have any tumor where you get 50% shrinkage when you use a checkpoint inhibitor,” he said. “What this means is, in spite of all the hype, the majority of patients actually don’t derive a lot of benefit. Why is this?”

He said one possibility is that the small minority of tumors that respond are inflamed; they could have mutations, DNA damage and more. For these tumors, an anti-PD-1 or anti-PD-L1 inhibitor would be effective.

Clinic researchers also began to explore the possibilities of oncolytic viruses in these tumors. They are currently using the vesicular stomatitis virus, a blunt-shaped RNA virus pathogenic to pigs, horses and cattle.

“This is naturally transmitted by certain flies, and they aren’t really seen as pathogenic for humans,” he said. “When humans are exposed to this virus, they get a mild flu, and it’s transient.”

Adjei said promising studies have been conducted in which an oncolytic virus, the coxsackievirus (CVA21, CAVATAK), combined with pembrolizumab (Keytruda, Merck).

“This is a one-time infusion of the virus and then continue with the pembrolizumab,” he said.

These studies have shown that the combination was well-tolerated and showed promising signs of activity. It also yielded substantial increases in PD-L1 tumor levels.

“This is exciting,” Adjei said. “With the advent of immunotherapy, we have been working toward using oncolytic viruses to enhance the efficacy of these checkpoint inhibitors.” – by Jennifer Byrne

Disclosures: HemOnc Today could not confirm Adjei’s relevant financial disclosure at the time of publication.