Develop Ways to Overcome Cancer’s Resistance to Therapy

Cancer cells may develop the ability to rewire or reprogram themselves to become resistant to treatments that were previously effective. Drug resistance accounts for many cancer recurrences and associated deaths. Despite progress in understanding drug resistance over the last decade, knowledge gaps remain about the underlying biological causes of drug resistance and the design of cancer treatments to overcome it.

This recommendation aims to address these gaps through an interdisciplinary effort to identify targets for the development of new cancer treatments that prevent or overcome drug resistance. Research teams involved in this initiative will use new experimental models to comprehensively characterize sensitivities of drug resistant cancer cells using clinical samples taken before, during, and after treatment. In addition, the research teams will work to better understand the pathways and mechanisms that allow tumors to become resistant to a given treatment.

This national collaborative research will include both pediatric and adult tumor types and representation from minority and underserved populations, as each population may have resistance mechanisms that are unique.

Ultimately, the hope is that knowledge gained from this initiative will be used to develop more effective therapies—tailored to an individual’s condition—to overcome treatment resistance, as well as to identify biomarker signatures that will guide different cancer treatment options to prevent the development of drug resistance.

NCI has awarded funding to several research projects that align with this recommendation’s goal to overcome drug resistance:

Drug Resistance and Sensitivity Network (DRSN)

NCI has created a network of drug resistance and sensitivity research centers, which is developing new experimental models for studying drug resistance in tumors, investigating mechanisms of drug resistance in cancer, and designing innovative approaches to exploit the sensitivity of cancer cells to specific treatments. This consortium includes teams of cancer biologists, computational scientists, clinicians, and model developers who are performing bench-to-bedside studies of cancer drug resistance and sensitivity. DRSN researchers are also involved in collaborative studies with investigators outside of the research consortium. These cooperative projects expand the network’s reach and promote data and resource sharing for understanding cancer drug resistance. 

Highlights of DRSN Research Progress

One Drug Resistance and Sensitivity Center (DRSC) has performed single-cell RNA sequencing on metastatic lung cancer tissue to reveal how adaptation caused by therapy shapes clinical outcomes for patients with lung cancer.

Another DRSC studied samples from patients with drug-resistant gastrointestinal cancers and found that clinically relevant mutations could be identified more frequently in cell-free DNA collected through liquid biopsies than in tissue biopsy samples.

Along with research contributions, the network is also building a collection of resources that can be used by the cancer researchers examining mechanisms of drug resistance. For example, a DRSC has created a "direct-to-drug" screening resource to evaluate the efficacy of 76 FDA-approved drugs on dozens of multiple myeloma cell lines and over 100 samples. Paired with functional genomics, this resources has the potential to improve personalized therapies for patients with multiple myeloma, which are desperately needed as most of these cancers relapse and become resistant to multiple drugs.

The findings and models from this collaborative multidisciplinary network will inform the design of new clinical cancer treatments that can prevent or overcome drug resistance to existing cancer therapies.

ViPOR-P: A Protocol for a Novel Treatment Combination in Patients with Relapsed or Refractory B-Cell Lymphoma

While there have been significant advances in the treatment of aggressive B-cell lymphomas, patients with disease that resists treatment have poor outcomes with standard therapies and indolent lymphomas remain most incurable. NCI recently launched the ViPOR-P trial to test combinations of drugs that target parallel cell-survival pathways as a way to overcome therapeutic resistance in patients with B-cell lymphomas.

Drug Resistance Projects Awarded Cancer Moonshot Funding

Awarded Projects