Novel Treatment Strategy Could Overcome Resistance

Douglas Lauffenburger, PhD

A preclinical study has shown promising steps toward tackling drug resistance in hematologic malignancies using sequential dosing of drugs targeted against vulnerabilities that emerge as a result of tumor evolution, according to data presented at a special AACR conference focused on hematologic malignancies.

“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,” study author Douglas Lauffenburger, PhD, professor in the Department of Biological Engineering and Koch Institute for Integrative Cancer Research at MIT in Boston, said in a statement. “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.”

Lauffenburger, along with colleagues Boyang Zhao and Michael Hemann, conducted a screening experiment using a combination of computational and experimental approaches to identify drugs that were likely to be effective against a murine acute lymphoblastic leukemia (ALL) cell line. In order to develop drug combinations based on the characteristics of evolving tumors, the researchers then used escalating doses of the drugs imatinib, dasatinib, nilotinib, foretinib, and crizotinib on ALL cells.

Following frontline treatment with an active agent, each cell line was split into two groups. Group A received different sets of drugs assessed at specific time points, while group B received treatment with the same drug that was used in the frontline setting at an escalated dose.

In the murine Bcr-Abl cell lines, crizotinib demonstrated similar efficacy to imatinib, with similar in vivo efficacy between the two drugs for overall survival. Moreover, cell cycle profiles and signaling analyses suggested that crizotinib induces G2/M arrest and apoptosis, a phenotype that was also validate in human K562 Philadelphia chromosome-positive CML, murine Baf3 Bcr-Abl wild-type, and Bcr-Abl T315I-mutated cell lines.

Crizotinib demonstrated similar efficacy in wild-type ALL cell lines as in those with the Bcr-Abl T315I resistance mutation. As expected, the same T315I cell line was resistant to treatment with imatinib, dasatinib, nilotinib, and bosutinib.

“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,” Lauffenburger said. “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.”

Cell lines treated with frontline dasatinib followed by a single dose escalation were more sensitive to crizotinib and foretinib, as a result of tumor heterogeneity. However, continued dose escalations of dasatinib cancelled this added sensitivity, suggesting distinct stages of tumor evolution when specific drugs might be more effective.

“It would be ideal to treat an ALL patient with dasatinib followed by crizotinib/foretinib for synergy during the early stages of clonal evolution of the patient’s tumor, rather than treating only with dasatinib and waiting until the patient has relapsed,” Lauffenburger said.

While promising, these findings are yet to be confirmed in larger randomized clinical trial. Moreover, at this point, the ALK inhibitor crizotinib is not an approved therapy for the treatment of patients with ALL.

“These findings suggest a novel combination treatment strategy taking into account the evolutionary trajectories of tumor heterogeneity, with drugs dosed sequentially in a multi-course regimen,” the authors wrote. “The sequential treatment is not to exploit vulnerabilities of intracellular rewiring induced by the first drug, but rather vulnerabilities of resulting expanded subpopulations upon selection by the first drug.”

Zhao B, Hemann MT, Lauffenburger DA. Combination therapies guided by evolution of tumor heterogeneity. Presented at: AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA.