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      Tumor Evolution as a Therapeutic Target

      Author(s): , ,
      Publication date Created:
      Publication date (Electronic):
      Journal: Cancer Discovery
      Publisher: American Association for Cancer Research (AACR)

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          Abstract

          Recent technological advances in the field of molecular diagnostics (including blood-based tumor genotyping) allow the measurement of clonal evolution in patients with cancer, thus adding a new dimension to precision medicine: time. The translation of this new knowledge into clinical benefit implies rethinking therapeutic strategies. In essence, it means considering as a target not only individual oncogenes but also the evolving nature of human tumors. Here, we analyze the limitations of targeted therapies and propose approaches for treatment within an evolutionary framework.

          Significance: Precision cancer medicine relies on the possibility to match, in daily medical practice, detailed genomic profiles of a patient's disease with a portfolio of drugs targeted against tumor-specific alterations. Clinical blockade of oncogenes is effective but only transiently; an approach to monitor clonal evolution in patients and develop therapies that also evolve over time may result in improved therapeutic control and survival outcomes. Cancer Discov; 7(8); 805–17. ©2017 AACR.

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          PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

          Dung Le, Jennifer Uram, Hao Wang … (2015)
          Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.
          Article 0 comments Cited 2526 times – based on 0 reviews     Review now
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            Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

            Marco Gerlinger, Andrew J Rowan, Stuart Horswell … (2012)
            Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).
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              Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

              Hannah L. Farmer, Nuala McCabe, Christopher J. Lord … (2005)
              BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
              Article 0 comments Cited 1092 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Title: Cancer Discovery
                Publisher: American Association for Cancer Research (AACR)
                ISSN (Print): 2159-8274
                ISSN (Electronic): 2159-8290
                Publication date Created: August 01 2017
                Publication date Created: August 1 2017
                Publication date (Print): August 01 2017
                Publication date (Electronic): August 1 2017
                Volume: 7
                Issue: 8
                Pages: 805-817
                Article
                DOI: 10.1158/2159-8290.CD-17-0343
                PubMed ID: 28729406
                SO-VID: d6848c2f-f77b-46ac-94a3-5d0a8742eed7
                Copyright © © 2017
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