Paradigm Shift in Cancer Research Development: The NCI ALMANAC (A Large Matrix of Antineoplastic Agent Combinations)
Hetalkumari Patel, PharmD BCOP
Pharmacy Clinical Coordinator, Hematology/Bone Marrow Transplant
University of Texas Southwestern–Simmons Comprehensive Cancer Center
Dallas, TX
Stefanie Conley, PharmD
Pharmacy Clinical Coordinator, Oncology–Investigational Drug Service
University of Texas Southwestern–Simmons Comprehensive Cancer Center
Dallas, TX
The National Cancer Institute (NCI) Developmental Therapeutics Program started more than 50 years ago with a mission to discover and develop novel anticancer agents. It makes several resources available to researchers to assist in drug discovery and development. Two such resources are the NCI-60, which has been available for about 25 years, and now the NCI ALMANAC. The NCI-60 contains human tumor cell lines and has been pivotal in helping create the NCI ALMANAC. Without the NCI-60, the ALMANAC might not have been created.1,2 The ALMANAC database contains information based on the testing of these cell lines with various combination drug therapies and is a tool that expedites the discovery of combination therapies. Two phase 1 trials have been developed so far using the ALMANAC database, one for triple negative breast cancer and the other for relapsed solid tumors.3
The emergence of resistant subpopulation clones are due in part to the inherent heterogeneity of tumors, and therefore it is imperative to discover new combination therapies.4 Investigators have been testing combinations of drugs for the treatment of cancer since the late 1950s, when drug combinations were first used for treatment of testicular cancer and other tumors.5 Because of the numerous Food and Drug Administration (FDA)–approved drugs available for various cancers, the rate at which an investigator can successfully find a novel therapeutic combination that is considered safe and effective is hindered by lack of time, money, and intellectual property rights. The ALMANAC database should allow investigators to accelerate their search for potential combination therapies for cancers like leukemia and solid tumors including melanoma, and those of the lung, brain, breast, ovary, prostate, and kidney.1,2
For example, a patient newly diagnosed with acute myelogenous leukemia with an FLT3 mutation may initially respond to therapy but may develop another mutation that did not exist at the time of the initial diagnosis. This second mutation may cause the growth of a different clone that becomes the predominant type in a relapsed or refractory setting. After the new mutation has been identified, one must question whether the mutation can be targeted and whether treatment with a combination therapy would decrease the chance of resistance or development of another mutation.
Using a database containing multiple combinations of FDA-approved oncology drugs that have been tested with a certain type of cell line could be the answer. If combinations of drugs that target cancer cells at different pathways within the same tumor can be identified, that regimen may overcome the mutated pathway, leading to a treatment response. The NCI ALMANAC, which became available to the public in May 2017, contains more than 5,000 combinations of 104 FDA-approved anticancer drugs that potentially have a therapeutic effect on cancer cell lines in vitro.6
The NCI-60 consists of 60 different human tumor cell lines that can be used to test novel compounds that can either kill the tumor cell line or inhibit growth. The cell lines include leukemia, melanoma, and cancers of the lung, colon, brain, breast, ovary, prostate, and kidney.1,2 Each cell line has been characterized extensively at the molecular level. These cell lines also examine multiple mechanisms for drug resistance; these include, but are not limited to, mutations or amplifications of the gene-encoding target, enhanced drug efflux or metabolism, activation of signaling networks that bypass the target, changes in deoxyribonucleic acid damage response or epigenetic pathways, and alterations in tumor microenvironment.7
When a single compound is tested against these tumor cell lines, a biologic response, if one exists, can be ascertained. By testing pairs of drugs, researchers have been able to create a database that shows activity of the FDA-approved drugs. Each drug in each pair was tested at different concentrations, producing more than 3 million data points.6
The NCI ALMANAC database tests novel drug combinations or drug combinations that have already been used in a subtype of cancer. The activity of the combination therapy is reported as a ComboScore. A positive ComboScore indicates strong activity in the tested pair as compared to each individual drug activity against the cell line. This is reported as a heat map where one can quickly visualize results to dose-response graphs.3
The decision to proceed with testing in vivo depended on three factors: clinical utility, ability for the cell lines to grow in xenograft implants, and the ComboScore. Hence in-vitro combination testing did not always result in in-vivo testing because of the sheer volume of combinations. Twenty novel combinations were chosen for greater than single-agent efficacy in one or more xenograft models derived from the NCI-60.3
One combination that showed increased activity in vivo has led to a phase 1 clinical trial. Clofarabine and bortezomib given in combination are being studied in adults with relapsed solid tumors (NCT02211755). These drugs have already gained FDA approval for hematologic malignancies individually but have not shown significant activity as monotherapy for solid tumors in previous testing.3
The NCI ALMANAC can be found on the NCI website and is available to the public.8 The database can be searched in four ways: using the heat map with results from all pairs tested, selecting two specific drugs tested, selecting a specific drug and a specific modifier mechanism, or generating a heat map for a particular drug against all tested specific modifier mechanisms.8
The NCI ALMANAC is a good example of what collaboration between government and private organizations can achieve for the advancement of cancer treatment. Easy access to the resource should expedite bench to bedside research for cancer patients.
References
1. Holbeck SL, Collins JM, Doroshow JH. Analysis of Food and Drug Administration-approved anticancer agents in the NCI-60 panel of human tumor cell lines. Mol Cancer Ther. 2010; 9(5):1451-1460.
2. National Cancer Institute. NCI-60 Human Tumor Cell Lines Screen. Available from https://dtp.cancer.gov/discovery_development/NCI-60.
3. Holbeck S, Camalier R, Crowell JA, et al. The National Cancer Institute ALMANAC: A comprehensive screening resource for the detection of anticancer drug pairs with enhanced therapeutic activity. Cancer Research. 2017;77(13):3564-3576.
4. Chen S-H, et al. Two is better than one: toward a rational design of combinatorial therapy. Curr Opin Struc Biol. 2016;41:145-150.
5. Devita V, et al. The use of drugs in combination for the treatment of cancer: rationale and results. N Engl J Med. 1973;288:998-1006.
6. Doroshow J, Collins J. (2017, May 12). NCI ALMANAC: A new tool for research on cancer drug combinations [Blog post]. Retrieved from https://www.cancer.gov/news-events/cancer-currents-blog/2017/nci-almanac-drug-combinations.
7. Rebucci M, et al. Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol. 2013;85:1219-1226.
8. National Cancer Institute. NCI ALMANAC Study Results. Available from https://dtp.cancer.gov/ncialmanac/initializePage.do