Editors' ChoiceCancer

New connections: Integrated search for therapies

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Science Signaling  25 Sep 2018:
Vol. 11, Issue 549, eaav4963
DOI: 10.1126/scisignal.aav4963

Integrating “omics” analyses with developmental models reveals therapeutic targets for aggressive cancers.

Advances in analytical, molecular, and biochemical technologies have enabled a “multi-omic” approach to cancer research, giving biologists and clinicians a wider and deeper view of tumors’ genetic and proteomic landscapes. Simultaneously, advances in single-cell and animal model research have revealed that various cancers have developmental origins, associated with the proliferation of stem-like progenitor cells in the affected tissue. Two studies integrate these technologies and methods to examine the developmental timings, origins, and drivers of two aggressive cancers for which few therapies currently exist. Stewart et al. performed genomic, epigenomic, and proteomic analysis on two models of rhabdomyosarcoma (RMS), an aggressive pediatric cancer that arises in skeletal muscle. Their findings revealed that RMS cells had aberrant activity in various pathways (including the RAS–MEK–ERK–CDK4/6 pathway, the unfolded protein response pathway, and mitotic checkpoint pathways). Of the various drugs tested, a combination of chemotherapy with an inhibitor of the kinase WEE1 (which perturbs the mitotic checkpoint) was the most effective at blocking the growth of orthotopic patient-derived xenografts in mice. Additionally, epigenomic and genomic analyses indicated that alveolar RMS (or ARMS, of which many express FOXO1:PAX3 fusion protein) emerged further along the muscle development program than embryonal RMS, revealing potentially useful diagnostic markers and additional targets for patients with these distinct types of RMS. The findings may lead to more targeted, subtype-specific therapies for patients with RMS.

In the Archives of Science Signaling, Purzner et al. performed phosphoproteomics in a developmental mouse model of medulloblastoma (MB). In murine granule neuron precursors (GNPs), the developmental cell of origin of MB, the protein kinase CK2 mediated many phosphorylation events during the proliferative, MB-like stage of GNP growth, including that of three proteins that are commonly amplified in MB. CK2 promoted the stabilization and activity of the transcription factor GLI2, an effector in sonic hedgehog (SHH) signaling. The SHH-driven subtype of MB is particularly aggressive and drug-resistant. CK2 inhibitors blocked the growth of SHH-type human and mouse MB cells and markedly extended the survival of tumor-bearing mice, in which the drug was well tolerated. One of the compounds also blocked the growth of tumors that had mutant CK2, suggesting that it is less susceptible to a common mode of drug resistance. A clinical trial testing the drug in pediatric patients is under way. These studies, both of which involved numerous researchers across the nation and the world (for Purzner et al.), highlight the utility of cross-disciplinary and cross-institute collaboration to move cancer research forward in meaningful ways for patients.

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