bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023‒11‒19
eleven papers selected by
Sergio Marchini, Humanitas Research

  1. Diagnostics (Basel). 2023 Oct 24. pii: 3293. [Epub ahead of print]13(21):
      Homologous recombination deficiency (HRD) has become an important prognostic and predictive biomarker for patients with high-grade serous ovarian cancer who may benefit from poly-ADP ribose polymerase inhibitors (PARPi) and platinum-based therapies. HRD testing provides relevant information to personalize patients' treatment options and has been progressively incorporated into diagnostic laboratories. Here, we assessed the performance of an in-house HRD testing system deployable in a diagnostic clinical setting, comparing results from two commercially available next-generation sequencing (NGS)-based tumor tests (SOPHiA DDMTM HRD Solution and AmoyDx® (HRD Focus Panel)) with the reference assay from Myriad MyChoice® (CDx). A total of 85 ovarian cancer samples were subject to HRD testing. An overall strong correlation was observed across the three assays evaluated, regardless of the different underlying methods employed to assess genomic instability, with the highest pairwise correlation between Myriad and SOPHiA (R = 0.87, p-value = 3.39 × 10-19). The comparison of the assigned HRD status to the reference Myriad's test revealed a positive predictive value (PPV) and negative predictive value (NPV) of 90.9% and 96.3% for SOPHiA's test, while AmoyDx's test achieved 75% PPV and 100% NPV. This is the largest HRD testing evaluation using different methodologies and provides a clear picture of the robustness of NGS-based tests currently offered in the market. Our data shows that the implementation of in-house HRD testing in diagnostic laboratories is technically feasible and can be reliably performed with commercial assays. Also, the turnaround time is compatible with clinical needs, making it an ideal alternative to offer to a broader number of patients while maintaining high-quality standards at more accessible price tiers.
    Keywords:  BRCA1/2; DNA repair; biomarkers; homologous recombination deficiency (HRD); next generation sequencing (NGS); ovarian cancer; poly (ADP–ribose) (PARP) inhibitors (PARPi)
  2. Cell Stress. 2023 Nov;7(11): 95-104
      Adoptive cell therapy (ACT) can successfully treat hematopoietic cancers but lacks efficacy against solid tumors. This is due to insufficient T cell infiltration, high tumor heterogeneity, frequent antigen loss with subsequent tumor escape, and the immunosuppressive tumor microenvironment (TME). Alternative methods to boost the anticancer efficacy of adoptively transferred cells are actively pursued. Among adjuvants that are utilized to stimulate anticancer immune responses, ligands of the stimulator of interferon genes (STING) pathway have received increasing attention. STING activation can trigger dendritic cell (DC) activation and endogenous immune responses, thereby preventing tumor escape. Activation of the STING pathway in the context of ACT was accordingly associated with improved T cell trafficking and persistence in the TME combined with the reduced presence of immunosuppressive cells. Recent findings also suggest cell-intrinsic effects of STING ligands on T cells. Activation of the STING signaling pathway was in this regard shown to enhance effector functions of CD4+ and CD8+ T cells, suggesting that the STING signaling could be exploited to harness T cell anticancer functions. In this review, we will discuss how the STING signaling can be used to enhance the anticancer efficacy of ACT.
    Keywords:  Adoptive T cell therapy; STING; T cells; cancer; immunomodulation
  3. Clin Exp Med. 2023 Nov 15.
      Epithelial-mesenchymal transition (EMT) is a dynamic program crucial for organismal development and tissue regeneration. Unfortunately, this program is often hijacked by epithelial tumors to facilitate metastasis. Beyond its role in cancer spread, EMT increases cancer cell survival by activating stem cell programs and bypassing apoptotic programs. Importantly, the capacity of EMT to enforce tumor progression by altering the tumor cell phenotype without triggering immune responses opens the intriguing possibility of a mechanistic link between EMT-driven cancers and immune evasion. Indeed, EMT has been acknowledged as a of driver immune evasion, but the mechanisms are still evolving. Here, we review recent insights into the influence of EMT on tumor immune evasion. Specifically, we focus on the mechanistic roles of EMT in immune escape as the basis that may provide a platform for innovative therapeutic approaches in advanced tumors. We summarize promising therapeutic approaches currently in clinical trials and trending preclinical studies aimed at reinvigorating the tumor microenvironment to create immune-permissive conditions that facilitates immune-mediated tumor clearance. We anticipate that this will assist researchers and pharmaceutical companies in understanding how EMT compromises the immune response, potentially paving the way for effective cancer therapies.
    Keywords:  Cytotoxic T lymphocyte; Epithelial–mesenchymal transition; Immune evasion; Immunotherapy; NK cells; Tumor microenvironment
  4. Diagnostics (Basel). 2023 Oct 28. pii: 3331. [Epub ahead of print]13(21):
      Tubo-ovarian cancer is the most lethal gynaecological cancer. More than 75% of patients are diagnosed at an advanced stage, which is associated with poorer overall survival. Symptoms at presentation are vague and non-specific, contributing to late diagnosis. Multimodal risk models have improved the diagnostic accuracy of adnexal mass assessment based on patient risk factors, coupled with findings on imaging and serum-based biomarker tests. Newly developed ultrasonographic assessment algorithms have standardised documentation and enable stratification of care between local hospitals and cancer centres. So far, no screening test has proven to reduce ovarian cancer mortality in the general population. This review is an update on the evidence behind ovarian cancer diagnostic strategies.
    Keywords:  biomarkers; diagnosis; imaging; ovarian cancer; screening
  5. Curr Treat Options Oncol. 2023 Nov 17.
      OPINION STATEMENT: Malignant pleural mesothelioma (MPM) is an aggressive asbestos-associated thoracic malignancy that is usually incurable. As demonstrated in the landmark MARS2 trial, surgical resection does not improve survival outcomes and its role in managing MPM is limited. Whilst platinum-pemetrexed chemotherapy in combination with bevacizumab was the standard first-line approach for unresectable disease, landmark phase 3 trials have now established the role of immune checkpoint inhibitors (CPIs) in the upfront management of unresectable disease: either nivolumab-ipilimumab or carboplatin-pemetrexed-pembrolizumab. Patient selection for optimal strategy remains an ongoing question. For relapsed disease novel genomic-based therapies targeting a range of aberrations including losses of the tumour suppressor genes BAP1, CDKN2A and NF2, are being evaluated. Nonetheless, the future of MPM therapeutics holds promise. Here we overview current treatment strategies in the management of MPM.
    Keywords:  Chemoimmunotherapy; Genomic driven therapy; Mesothelioma; Peri-operative therapy; Radiotherapy; Surgery
  6. Nat Med. 2023 Nov 16.
    Keywords:  Microbiome; Reproductive biology; Sequencing
  7. Cancer Res. 2023 Nov 14.
      Plasticity refers to the ability of cells to adopt a spectrum of states or phenotypes. In cancer, it is a critical contributor to tumor initiation, progression, invasiveness, and therapy resistance, and it has recently been recognized as an emerging cancer hallmark. Plasticity can occur as a result of cell-intrinsic factors (e.g. genetic, transcriptional or epigenetic fluctuations), or through cell-extrinsic cues (e.g. signaling from components of the tumor microenvironment (TME) or selective pressure from therapy). Over the past decade, technological advances, analysis of patient samples, and studies in mouse model systems have led to a deeper understanding of how such plastic states come about. In this review, we discuss: (i) the definition of plasticity; (ii) methods to measure and quantify plasticity; (iii) the clinical relevance of plasticity; and (iv) therapeutic hypotheses to modulate plasticity in the clinic.
  8. Cancer Treat Res. 2023 ;186 285-298
      Polymerase theta (POLθ) is the critical multi-domain enzyme in microhomology-mediated end-joining DNA double-stranded break repair. POLθ is expressed at low levels in normal tissue but is often overexpressed in cancers, especially in DNA repair deficient cancers, such as homologous-recombination cancers, rendering them exquisitely sensitive to POLθ inhibition secondary to synthetic lethality. Development of POLθ inhibitors is an active area of investigation with inhibitors of the N-terminal helicase domain or the C-terminal polymerase domain currently in clinical trial. Here, we review POLθ-mediated microhomology-mediated end-joining, the development of POLθ inhibitors, and the potential clinical uses of POLθ inhibitors.
    Keywords:  MMEJ; POLQ; Polymerase theta; Synthetic lethality
  9. Int J Mol Sci. 2023 Nov 02. pii: 15907. [Epub ahead of print]24(21):
      Over the course of long-term evolution, cells have developed intricate defense mechanisms in response to DNA damage; these mechanisms play a pivotal role in maintaining genomic stability. Defects in the DNA damage response pathways can give rise to various diseases, including cancer. The DNA damage response (DDR) system is instrumental in safeguarding genomic stability. The accumulation of DNA damage and the weakening of DDR function both promote the initiation and progression of tumors. Simultaneously, they offer opportunities and targets for cancer therapeutics. This article primarily elucidates the DNA damage repair pathways and the progress made in targeting key proteins within these pathways for cancer treatment. Among them, poly (ADP-ribose) polymerase 1 (PARP1) plays a crucial role in DDR, and inhibitors targeting PARP1 have garnered extensive attention in anticancer research. By delving into the realms of DNA damage and repair, we aspire to explore more precise and effective strategies for cancer therapy and to seek novel avenues for intervention.
    Keywords:  DNA damage response; DNA repair; PARP1; cancer therapy; double-strand DNA break repair
  10. Cancers (Basel). 2023 Oct 24. pii: 5116. [Epub ahead of print]15(21):
      BACKGROUND: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design.METHODS: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments.
    RESULTS: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors.
    CONCLUSIONS: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
    Keywords:  in silico analysis; malignant pleural mesothelioma; multiplex immunofluorescence; prognosis; transcriptoma
  11. Med. 2023 11 10. pii: S2666-6340(23)00260-X. [Epub ahead of print]4(11): 755-760
      Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a multidisciplinary approach aimed at gaining novel therapeutic insights by focusing on the poorly understood minimal residual disease phase of ovarian cancer that leads to eventual incurable recurrences.