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Drug release in a cancer cell
Credit: PNAS

PHILADELPHIA—A combination treatment strategy that takes tumor evolution into account could help us avoid drug resistance in hematologic malignancies, researchers say.

Preclinical experiments suggest we can prevent resistance by starting secondary treatment prior to relapse.

For example, a patient receiving dasatinib for acute lymphoblastic leukemia (ALL) could benefit from receiving crizotinib or foretinib during the early stages of clonal evolution.

The researchers described this strategy in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“Our goal is to identify vulnerabilities in cancer across stages of tumor evolution while it is developing resistance to initial treatment, to help guide the design of drug combination strategies,” said Douglas Lauffenburger, PhD, of the Koch Institute for Integrative Cancer Research at MIT in Boston.

“There may be many stages in a tumor evolution while under treatment that may make them vulnerable to already existing therapies. Rather than waiting for the tumor to become resistant to the first treatment and then thinking about a second-line drug to use, we can capitalize on opportunities that exploit vulnerabilities at different early stages, as the tumor is evolving to become resistant to the first drug.”

Dr Lauffenburger and his colleagues used a combination of computational and experimental approaches to identify drugs likely to be effective against a murine ALL cell line as the cells evolve.

To develop drug combinations based on the characteristics of evolving tumors, the researchers used escalating doses of imatinib, dasatinib, nilotinib, foretinib, and crizotinib on ALL cells.

As some cells exhibited resistance to a particular drug, the team treated the resistant cells with other drugs to check for cross-resistance. They found that resistant cells surviving at low multiples of the original drug dose actually demonstrated sensitization to certain other drugs, with the sensitization abrogated at higher doses.

Specifically, cell populations that were resistant to dasatinib at 1x and 2x IC90 became even more sensitive to crizotinib and foretinib. However, the sensitivity was lost at IC90 4x and above.

“Instead of only looking for the most resistant population of ALL cells at the end of this selection process, we monitored for drug sensitivity of the cells at each stage of the dose escalation,” Dr Lauffenburger explained.

“This led us to discover the vulnerabilities of a tumor at different stages of clonal evolution, a phenomenon we would have missed if we only analyzed for drug sensitivity at the last stage of this process, which is equivalent to when a patient has relapsed.” ht-logo-end

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