Two is better than one; toward a rational design of combinatorial therapy

Abstract

Drug combination is an appealing strategy for combating the heterogeneity of tumors and evolution of drug resistance. However, the rationale underlying combinatorial therapy is often not well established due to lack of understandings of the specific pathways responding to the drugs, and their temporal dynamics following each treatment. Here we present several emerging trends in harnessing properties of biological systems for the optimal design of drug combinations, including the type of drugs, specific concentration, sequence of addition and the temporal schedule of treatments. We highlight recent studies showing different approaches for efficient design of drug combinations including single-cell signaling dynamics, adaption and pathway crosstalk. Finally, we discuss novel and feasible approaches that can facilitate the optimal design of combinatorial therapy.

The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

“…B , nilotinib/paclitaxel combination treatment exhibits enhanced efficacy relative to the respective single-agent treatments in the MDA-MB-468 triple-negative breast cancer xenograft model. Median tumor volumes are shown for mice treated with vehicle, single-agent nilotinib (75 mg/kg QDx5, PO for 4 cycles beginning on days 25, 32, 39, and 46), single-agent paclitaxel (on one of two dose schedules for 2 cycles beginning on days 25 and 39: [1] 15 mg/kg, Q7Dx2, IV; or [2] 10 mg/kg, QDx3, IV); or [3] the respective combinations (schedule and administration as indicated for the respective single-agent treatments; dosing period indicated by gray-shaded area). n = 15 mice for vehicle group, and n = 7–8 mice for all other groups.…”

“…Recognizing that combining anticancer drugs—whether cytotoxic or molecularly targeted—with distinct mechanisms of action is the approach most likely to overcome single-agent resistance and produce sustained clinical remissions (2,3), we determined that it would be of value to systematically screen pairwise combinations of 104 US Food and Drug Administration (FDA)-approved oncology drugs in the NCI-60 panel of human tumor cell lines. Our objective was to create a database, the NCI-ALMANAC ( A L arge M atrix of A nti N eoplastic A gent C ombinations), that could be searched to identify combinations with greater antitumor activity than either agent alone.…”

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

“…The combination of two or more drugs targeting different cancer pathways is now being actively pursued [43][44][45][46] . This approach creates synergistic effects able to reduce the emergence of tumour recurrence and resistance, since cancer cells are most likely incapable of adapting to the simultaneous effects of two therapeutic agents [47][48][49][50][51] . However, a combination therapy does not exclude side effects in treated patients, disclosing the need for a combination therapy made by standard chemotherapy and biological drugs.…”

Looking beyond the cancer cell for effective drug combinations

“…Combination therapies aimed at reducing the plasticity of tumor cells, synchronizing the cell cycle or otherwise maintaining sensitized tumor cell states, or targeting epigenetic dysregulation hold additional promise for the prevention of drug resistance and tumor evolution [3, 21, 22]. For example, enhanced or prolonged tumor responses have been reported using drug combinations that inhibit DNA repair to sensitize tumor cells to DNA-damaging agents [23]; target epigenetic regulators to prevent cell state transition [15]; or synchronize the cells’ DNA repair cycle at a point that is sensitive to chemotherapy [24].…”

“…Secondary management of chronic obstructive pulmonary disease in patients with lung cancer can prevent health deterioration and prolong administration of anticancer agents [58]. Creative intermittent scheduling and switching of therapies can help to avoid toxicities while maintaining pharmacodynamically effective doses [3, 22]. The advent of biosensors and other advanced technologies for real-time monitoring [58–60] offers an unprecedented opportunity to manage a patient’s wellness throughout their cancer care and maximize therapeutic efforts.…”