Researchers have identified a new strategy to approach resistance to therapies for patients with hematologic cancers-treating the malignancies upfront with a sequence of treatments that exploit the vulnerabilities of these cancer types.
Researchers have identified a new strategy to approach resistance to therapies for patients with hematologic cancers-treating the malignancies upfront with a sequence of treatments that exploit the vulnerabilities of these cancer types. These results were presented at a teleconference at the American Association of Clinical Research (AACR) conference: Hematologic Malignancies: Translating Discoveries to Novel Therapies, held Sept. 20-23, 2014, in Philadelphia.
Douglas A. Lauffenburger, PhD, professor of biological engineering at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology and colleagues, sought to identify novel ways to target the cancers as these cancers evolve and develop resistance, and further heterogeneity as a result of exposure to drugs.
The researchers screened drug candidates using computational and bench top approaches, identifying drugs that could target a mouse acute lymphoblastic leukemia (ALL) cell line and a human chronic myelogenous leukemia (CML), including crizotinib (Xalkori)--an ALK (anaplastic lymphoma kinase) inhibitor--which had comparable efficacy to imatinib. Crizotinib also showed efficacy in a mouse model in BCR-ABL ALL that was resistant to BCR-ABL kinase inhibitors: imatinib, dasatinib, nilotinib, and bosutinib.
They next tested drug combinations of the kinase inhibitors, dasatinib, imatinib, nilotinib, foretinib, and crizotinib. The first three agents are approved for and target the BCR/ABL kinase in Philadelphia chromosome-positive ALL and CML. Foretinib is an investigational inhibitor of the c-Met and vascular endothelial growth factor receptor-2 (VEGFR-2) enzymes and crizotinib is an approved oral inhibitor that targets ALK, the ROS1 (c-ros oncogene 1), and the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase.
BCR-ABL ALL cells were exposed to escalating doses of imatinib, dasatinib, nilotinib, foretinib, and crizotinib and resistant population were isolated and characterized. Monitoring for drug sensitivity during drug dose escalation, the authors found that while the cell lines were resistant to some of the agents, they were sensitive to combinations with others, but only initial lower doses of dasatinib-initial higher doses of dasatinib abrogated the sensitivity. Those cells resistant to dastanib became even more sensitive to crizotinib and foretinib, but the sensitivity was diminished at higher doses of the combination treatment. The dasatinib-resistant cells also became resistant to the other BCR-ABL inhibitors.
“Treatment with dasatinib appears to sensitize these cells to the MET kinase targeting agents shortly after dasatinib therapy begins,” said Lauffenburger during the teleconference. Lauffenburger suggest that there is a time window between the initial rewiring of the cells, upon exposure to the initial therapy, and the re-emergence of subclones that occurs when the majority of cells become resistant to dasatinib. This time window may be exploited by treatment with a combination therapy to kill the subpopulation of cells not targeted by the BCR-ABL inhibitor.
The fine-tuned monitoring led the team to understand the vulnerabilities of these evolving cell lines at different clonal evolution stages rather than just at the end--equivalent to when a patient experiences relapse.
The cell line work showed that the ideal combination for ALL was dasatinib followed by crizotinib plus foretinib during the early evolution of ALL, rather than waiting to treat only until the cells were resistant to dasatinib. According to Lauffenburger, switching to a second therapy prior to the tumor cells developing resistance-within a week or two of starting the initial treatment-results in an overall lower rate of resistance because, at that point, only a small percentage of cells resistant to dasatinib (but are still sensitive to foretinib and crizotinib) can be targeted. But, waiting until the entire population is resistant to dasatinib likely results in further heterogeneity of resistance mechanisms.
The discovery of a so-called "intermediate time window that is longer than the initial drug-induced tumor cell reprogramming, but shorter than the typical re-emergence of tumor growth upon relapse was surprising," said Lauffenburger. “This (time window in the tumor cells’ evolution) can potentially be exploited by subpopulation sequencing of the original tumor population,” Lauffenburger told OncoTherapy Network.
The next step in this research, Lauffenburger told Oncotherapy Network, is to sequence the cell populations over time points during various treatment exposures to understand the spectrum of mutations that evolve. “This is to test our hypothesis about the heterogeneous subpopulation evolution,” Lauffenburger said. A second goal is to test the second drug exposure during the early evolution of the tumor in mouse models.
“This is a wonderful opportunity to exploit the biology of the cells that we know so far, that within patients there are multiple clones that are characterized by different genetic profiles,” said teleconference moderator Kenneth C. Anderson, MD, program director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, in Boston.