Small-Molecule Compound Shows Promise for Treating Drug-Resistant Tumors

The Topline 

  • ONC201/TIC10 is a compound that stimulates a pathway used by the immune system to suppress cancer and metastases, leading to tumor cell death
  • The compound has shown effects in brain tumors, as well as in colon, breast, and lung cancers, and lymphoma
  • Clinical trials are now being conducted on ONC201/TIC10, including one that recently opened at Fox Chase

A new compound called ONC201/TIC10 has entered clinical trials and may have the potential to treat various forms of drug-resistant cancers.

Through a screen of an NCI chemical library, Wafik S. El-Deiry, MD, PhD, FACP, professor of medical oncology and deputy director for translational research at Fox Chase Cancer Center, and his colleagues discovered ONC201/TIC10. Also known as TRAIL-inducing compound number 10, it is a compound that stimulates the recombinant tumor necrosis factor-related apoptosis-inducing ligand, which is a pathway used by the immune system to suppress cancer and its metastases—ultimately leading to tumor cell death.

“For a number of years, our laboratory has been interested in developing new strategies to kill tumor cells because there’s a real need for new treatments for drug-resistant cancers,” says El-Deiry, who is also an American Cancer Society research professor and co-leader of the Molecular Therapeutics Program at Fox Chase.

spheres-1-rev

Space filling 3D model for the structure of ONC201/TIC10. Images courtesy of Wafik El-Deiry

After the researchers’ discovery, initially published in Science Translational Medicine in 2013, studies in mice revealed that this first-in-class drug has a broad spectrum of anticancer activity and did not cause any apparent toxicities. El-Deiry and colleagues found that the compound can be administered orally and can cross the blood–brain barrier into the central nervous system, thereby leading to effects in brain tumors. “Some of our other experiments also showed effects in colon cancer, breast cancer, lung cancer, and lymphoma,” says El-Deiry.

Additional work published in Cancer Research in 2015 showed that the ONC201/TIC10 compound targets cancer stem cells. The researchers also conducted studies on predictive biomarkers and measurements in tumors or serum that can help to determine how well the compound is working.

Brain_cancer_sideClinical trials are now underway for ONC201/TIC10, including one led by Anthony J. Olszanski, MD, RPh, director of the Early Clinical Drug Development Phase I Program at Fox Chase. In the laboratory, El-Deiry and his colleagues will continue studying the compound’s detailed mechanism of action, its potential resistance mechanisms, and how to combine it with other chemotherapy agents as well as targeted chemotherapy.

“We’ve also been planning ahead for the next wave of clinical trials,” El-Deiry says. “Most drugs are ultimately used in combination therapy to treat cancer, and this takes a lot of work—some of it preclinical—to come up with the best design for clinical trials. Part of the motivation for combining drugs is not only to have a better therapeutic effect on the tumors, but also to delay or overcome any kind of resistance mechanisms.”

Also to support the clinical translation, El-Deiry and his team are investigating issues related to how the drug should be dosed.

“In the preclinical models, we have good data that indicate there is a broad range of tumors in which there is activity, and hopefully in the not-too-distant future, there will be clinical trials combining the new drug with other chemotherapy or targeted agents,” he says.

El-Deiry’s co-authors for the first Cancer Research study are Varun V. Prabhu, PhD, and David T. Dicker, both from Penn State Hershey Cancer Institute and Fox Chase; Mala Talekar, MD, A. Pieter J. van den Heuvel, PhD, Bora Lim, MD, Jennifer L. Fritz, and Adam Beck from Penn State Hershey Cancer Institute; and Joshua E. Allen from Oncoceutics, Inc.

El-Deiry’s co-authors for the second Cancer Research study are Varun V. Prabhu, PhD, and David T. Dicker, both from Penn State Hershey Cancer Institute and Fox Chase, and Joshua E. Allen from Oncoceutics, Inc.

 

Transcribed Chromatin Can “Sense” DNA Damage

New research suggests the existence of a novel, chromatin-
specific mechanism for detecting non-template DNA single strand breaks by transcribing RNA polymerase that relies on formation of multiple small intranucleosomal DNA loops.

Vasily M. Studitsky, PhD, co-leader of cancer epigenetics at Fox Chase Cancer Center, used nucleosomal DNA templates that contained NT-SSBs to evaluate the possibility that chromatin structure could affect the process repair of DNA damage. The research was published in Science Advances.

Studitsky and colleagues previously found that during transcription through chromatin, small intranucleosomal DNA loops are temporarily formed. The loops are stabilized by transient interactions of histones with Pol II—and ultimately resolved as Pol II progresses along the intact DNA.

When an NT-SSB is present in the loop, the structure of the complex changes and the Pol II stops, thus marking the damage.

SSBs that remain unrepaired can increase genomic instability and cell death. This could be used for prevention and perhaps treatment of diseases, according to the researchers.

Studitsky-rev

Structure of a putative small intranucleosomal DNA loop that transiently forms during transcription through intact chromatin by RNA polymerase II (Pol II). In the presence of ss-breaks in DNA, the structure of the loop (the level of stress in DNA structure) likely changes, preventing rotation of Pol II around DNA (blue arrow).
Image courtesy of Nadezhda Gerasimova.

In a healthy patient, if the process of loop formation by RNA polymerase were to become more efficient, then the patient would have a lower likelihood of developing related diseases. In contrast, if a patient already has a disease and a drug could be developed to selectively destabilize the interacting surface, this could lead to less efficient DNA repair and host cell apoptosis.