Getting the facts on FACT
BUFFALO, N.Y.—Pancreatic cancer is one of the most aggressive types of cancer, presenting with some of the worst survival rates. While chemotherapeutic regimens exist, patients with this cancer type are prone to drug resistance. As such, the publication of recent studies from Cleveland BioLabs Inc. and Roswell Park Cancer Institute detailing the efficacy of the small molecule CBL0137 in pancreatic cancer models could offer some hope for patients.
Studies detailing CBL0137’s preclinical efficacy appeared in Oncotarget in a paper titled “Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer.” Cleveland BioLabs and Roswell Park Cancer Institute are studying CBL0137 both as a monotherapy and in combination with gemcitabine, the current standard of care, in models of pancreatic ductal adenocarcinoma (PDA) and models of gemcitabine-resistant tumors. The studies were conducted by researchers at Roswell Park, SUNY Downstate Medical Center and Buffalo Biolabs, LLC.
CBL0137’s mechanism of action consists of the modulation of several important signaling pathways involved in the pathogenesis of PDA through the inhibition of the chromatin remodeling complex, known as FACT (Facilitates chromatin transcription), which is frequently overexpressed in several different tumor types. FACT-positive tumors are associated with an aggressive malignant phenotype—that is, a high-grade, metastatic disease with worse overall survival outcomes. As noted on Cleveland BioLabs’ website, “The interaction of CBL0137 with FACT complex results in simultaneous NF-kB suppression, Heat Shock Factor 1 suppression and p53 activation. This modulation of three key cellular pathways causes suppression of cancer cell growth.”
“The DNA in our cells is quite long; each chromosome is around more than one yard, and its length can be packed to be quite compact to fit into the nucleus of our cells and also to be well organized. So there are special protein complexes which help to pack this DNA,” explains Dr. Katerina Gurova, assistant professor of oncology in the Department of Cell Stress Biology at Roswell Park Cancer Institute. “FACT was considered to have this basic housekeeping-like function because people usually studied it in some unicellular organisms or in models using tumor cells, but when we looked more carefully, we found that FACT is present mostly in tumor cells, and in a very limited amount of normal cells. And it’s quite understandable, because probably this packaging and unpackaging of DNA is more critical for quickly proliferating tumor cells than for normal cells.”
The team studied CBL0137 as both a monotherapy and a combination therapy with gemcitabine using patient-derived PDA xenografts and PANC-1 orthotopic tumors. The compound was found to be efficacious in mouse models of PDA and to enhance the effect of gemcitabine by causing a significant delay in tumor relapse following treatment completion. It is thought that the combined results arise from CBL0137 targeting cancer stem cells while also modulating the expression of genes affecting gemcitabine sensitivity.
“We believe there are several mechanisms involved in combined toxicity,” says Gurova. “Gemcitabine targets quickly proliferating tumor cells, because it’s a compound which inhibits DNA synthesis. CBL0137 targets cancer stem cells, which are believed to be slowly proliferating … so when we combine them together, we are kind of targeting both populations of cells: quickly proliferating bulk tumor cells and slowly proliferating cancer stem cells. Plus there are additional mechanisms involved which just make cells more sensitive to gemcitabine.”
“As of today, CBL0137 has been shown efficacious in practically any cancer model tested. And we covered many dozens of in-vivo models of cancer, including all major cancers and many cancers that belong to more rare categories, meaning that we are not restricted to just one or two types of cancer. As Katerina mentioned, the expression of FACT is observed in cancer stem cells, again meaning that practically any type of cancer should be considered as a potential target for treatment with CBL0137,” says Dr. Andrei Gudkov, senior vice president of basic science at Roswell Park Cancer Institute and chief scientific officer of Cleveland BioLabs.
“These data reinforce our growing base of evidence regarding the potentially broad efficacy of Curaxin CBL0137’s mechanism of action. The data shared in this publication and the known role of FACT in the pathogenesis of PDA and viability of cancer stem cells support our consideration of pancreatic cancer as a potential indication for Phase 2 development of CBL0137,” he added.
Gudkov notes that hematological malignancies and brain tumors are also indications they are considering as they advance CBL0137, as the compound has proven capable of passing through the blood-brain barrier.
CBL0137 is undergoing two Phase 1 clinical trials. In the United States, Curaxin CBL0137 is being evaluated in patients with metastatic or unresectable advanced solid cancers and lymphomas in multiple centers, including Roswell Park Cancer Institute. A Phase 1 study investigating the oral administration of the compound in patients with advanced solid tumors that are resistant or refractory to current standard treatment is also underway.
“Pancreatic cancer is a very challenging disease that is highly resistant to conventional chemotherapy. CBL0137 has been shown to be effective in preclinical pancreatic cancer models, including gemcitabine-resistant tumors. The agent seems to target pancreatic cancer stem cells and survival pathways, thus rendering this a very promising treatment for this disease,” said Wen Wee Ma, associate professor of oncology in the Department of Medicine at Roswell Park Cancer Institute and principal investigator for the intravenous trial of CBL0137.
Pancreatic cancer stands as the fourth leading cause of cancer-related death in the United States, with the highest mortality rate of all major cancers: according to the American Cancer Society, 94 percent of pancreatic cancer patients will die within five years of diagnosis.