bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023–07–09
three papers selected by
Sergio Marchini, Humanitas Research
  1. Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials.
  2. Targeting the Tumor-Tumor Microenvironment Crosstalk.
  3. Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project.
  1. Oncol Res. 2023 ;31(4): 405-421
    Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials.
    Dhanya K Nambiar, Deepali Mishra, Rana P Singh.
      Ionizing radiation is frequently used to treat solid tumors, as it causes DNA damage and kill cancer cells. However, damaged DNA is repaired involving poly-(ADP-ribose) polymerase-1 (PARP-1) causing resistance to radiation therapy. Thus, PARP-1 represents an important target in multiple cancer types, including prostate cancer. PARP is a nuclear enzyme essential for single-strand DNA breaks repair. Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair (HR) pathway. This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications. We focused on the use of PARP inhibitors in various cancers, including prostate cancer. We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.
    Keywords:  BRCA mutations; DNA repair; PARP inhibitors; Synthetic lethality
    DOI:  https://doi.org/10.32604/or.2023.028310
  2. Expert Opin Ther Targets. 2023 Jul 04. 1-11
    Targeting the Tumor-Tumor Microenvironment Crosstalk.
    Sunil S Badve, Yesim Gökmen-Polar.
       INTRODUCTION: Cancer development and progression is a complex process influenced by co-evolution of the cancer cells and their microenvironment. However, traditional anti-cancer therapy is mostly targeted toward cancer cells. To improve the efficacy of cancer drugs, the complex interactions between the tumor (T) and the tumor microenvironment (TME) should be considered while developing therapeutics.
    AREAS COVERED: The present review article will discuss the components of T-TME as well as the potential to co-target these two distinct elements. We document that these approaches have resulted in success in preventing tumor progression and metastasis, albeit in animal models in some cases. Lastly, it is important to consider the tissue context and tumor type as these could significantly modify the role of these molecules/pathways and hence the overall likelihood of response. Furthermore, we discuss the potential strategies to target the components of tumor microenvironment in anti-cancer therapy. PubMed and ClinicalTrials.gov was searched through May 2023.
    EXPERT OPINION: The tumor-tumor microenvironment cross talk and heterogeneity are major mechanisms conferring resistance to standard of care. Better understanding of the tissue specific T-TME interactions and dual targeting has the promise of improving cancer control and clinical outcomes.
    Keywords:  Tumor; Tumor microenvironment; cancer progression; dual targeting; interactions; metastasis
    DOI:  https://doi.org/10.1080/14728222.2023.2230362
  3. Mol Cell. 2023 Jun 29. pii: S1097-2765(23)00465-3. [Epub ahead of print]
    Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project.
    Job Dekker, Frank Alber, Sarah Aufmkolk, Brian J Beliveau, Benoit G Bruneau, Andrew S Belmont, Lacramioara Bintu, Alistair Boettiger, Riccardo Calandrelli, Christine M Disteche, David M Gilbert, Thomas Gregor, Anders S Hansen, Bo Huang, Danwei Huangfu, Reza Kalhor, Christina S Leslie, Wenbo Li, Yun Li, Jian Ma, William S Noble, Peter J Park, Jennifer E Phillips-Cremins, Katherine S Pollard, Susanne M Rafelski, Bing Ren, Yijun Ruan, Yaron Shav-Tal, Yin Shen, Jay Shendure, Xiaokun Shu, Caterina Strambio-De-Castillia, Anastassiia Vertii, Huaiying Zhang, Sheng Zhong.
      The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and highlight the development of technologies for (1) mapping genome folding and identifying roles of nuclear components and bodies, proteins, and RNA, (2) characterizing nuclear organization with time or single-cell resolution, and (3) imaging of nuclear organization. With these tools, the consortium has provided over 2,000 public datasets. Integrative computational models based on these data are starting to reveal connections between genome structure and function. We then present a forward-looking perspective and outline current aims to (1) delineate dynamics of nuclear architecture at different timescales, from minutes to weeks as cells differentiate, in populations and in single cells, (2) characterize cis-determinants and trans-modulators of genome organization, (3) test functional consequences of changes in cis- and trans-regulators, and (4) develop predictive models of genome structure and function.
    Keywords:  4D nucleome; cell cycle; chromosome folding; development; disease model; genomics technologies; imaging technologies; modeling; nuclear organization
    DOI:  https://doi.org/10.1016/j.molcel.2023.06.018
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