AML drug may be good for KRAS-driven pancreatic cancer, computer-aided drug discovery finds
Clayton Boldt, Ph.D.
Repurposing FDA-approved therapies is a cost-effective way to bring new treatments to patients in need, but identifying those drugs with benefits in new indications can be a challenging discovery process.
A team of researchers led by MD Anderson and the IRCCS Regina Elena National Cancer Institute in Rome have used a novel computer-aided drug discovery approach to identify decitabine, an FDA approved therapy for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as a candidate for treating pancreatic cancers driven by mutations in the KRAS gene.
Pancreatic cancer is among the most lethal cancer types, with a five-year survival rate under 10%, due in part to a lack of effective therapies. Nearly all pancreatic cancers have a mutation in the KRAS gene, which leads to the activation of gene pathways that spur tumor growth. Unfortunately, despite broad efforts in the field, an effective KRAS inhibitor has yet to reach the clinic.
“One of the faster ways to discover new therapies is through precise repositioning of approved, safe therapies in novel indications,” says co-corresponding author Alessandro Carugo, Ph.D., Functional Genomics and Innovation Biology Group leader with MD Anderson’s TRACTION platform. “With this in mind, we leveraged a sophisticated approach of network pharmacology to identify approved therapies that could act as inhibitors of oncogenic KRAS.”
Algorithm points to decitabine for pancreatic cancer treatment
The researchers used an algorithm designed to analyze gene expression changes in response to drug treatment. By inputting a gene signature specific to KRAS-driven cancers, they identified drugs that could reverse those gene expression changes, thereby acting as KRAS inhibitors. This approach pointed to decitabine (5-aza-2'-deoxycytidine) as the top candidate.
Decitabine is an analogue of the nucleotide cytidine, a normal component of DNA. Upon treatment, decitabine is incorporated into DNA and disrupts essential chemical modifications, known as methylation, to the DNA backbone. This loss of methylation leads to the activation of previously silenced genome regions and increased gene expression.
To validate decitabine in this setting, the team utilized the translational biology capabilities of MD Anderson’s TRACTION platform, part of the institution’s Therapeutics Discovery division. This unique drug discovery and development engine within MD Anderson is advancing the next generation of cancer medicines from concept to clinical trial, all under one roof.
In cancer cell lines and mouse models of patient tumors, decitabine blocked cell proliferation, slowed tumor growth and reduced metastatic spread of the tumor. However, this effect was not ubiquitous for all pancreatic cancer models with KRASmutations, but only those cancers dependent on oncogenic KRAS.
“By exploiting the immense translational resources of the Therapeutics Discovery platforms, we were able to develop a refined signature to predictively stratify patients based on KRAS dependency, so that we can better position decitabine for pancreatic cancer patients most likely to benefit,” says Carugo.
Based on this signature, the authors estimate that 30-50% of patients with pancreatic cancer have KRAS-dependent tumors. Going forward, the researchers suggested these results warrant evaluation in clinical trials to determine if decitabine can provide clinical benefit to this patient population.
Additionally, there may be opportunities to evaluate this approach in alternative cancer types commonly driven by KRASmutations, such as lung and colorectal cancers. Work is ongoing to explore the response to decitabine in models of those diseases.
This study was supported with funding from the AACR Pancreatic Cancer Action Network and the Sewell Family Chair in Genomic Medicine. The Therapeutics Discovery platforms are supported by MD Anderson’s Moon Shots Program®, a collaborative effort to advance scientific discoveries into clinical advances that save patients’ lives.