bims-ovdlit 2021-05-16 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2021‒05‒16
twenty papers selected by
Lara Paracchini
Humanitas Research

Mutated circulating tumor DNA as a liquid biopsy in lung cancer detection and treatment.
Cancer-causing BRCA2 missense mutations disrupt an intracellular protein assembly mechanism to disable genome maintenance.
Liquid Biopsy in Breast Cancer: Circulating Tumor Cells and Circulating Tumor DNA.
Fragmentation of surgery and chemotherapy in the initial phase of ovarian cancer care and its association with overall survival.
Should we or should we not? Risk reduction bilateral salpingectomy for BRCA mutation carriers.
DNA Damage Repair Inhibitor for Breast Cancer Treatment.
High-throughput full-length single-cell RNA-seq automation.
The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target.
Comparison of dose-dense vs. 3-weekly paclitaxel and carboplatin in the first-line treatment of ovarian cancer in a propensity score-matched cohort.
Narrative review of cytoreductive surgery and intraperitoneal chemotherapy for peritoneal metastases in ovarian cancer.
Screening for ovarian cancer is ruled out after trial found it did not reduce deaths.
Application of artificial intelligence in gynecologic malignancies: A review.
Targeting the actin/tropomyosin cytoskeleton in epithelial ovarian cancer reveals multiple mechanisms of synergy with anti-microtubule agents.
Inhibition of sphingosine kinase 2 down-regulates ERK/c-Myc pathway and reduces cell proliferation in human epithelial ovarian cancer.
Low-grade serous epithelial ovarian cancer: a comprehensive review and update for radiologists.
Therapeutic targeting of chromatin: Status and opportunities.
Cytoreductive surgery followed by chemotherapy and olaparib maintenance in BRCA 1/2 mutated recurrent ovarian cancer: a retrospective MITO group study.
Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2.
The Role of Gut Microbiota in Modulating Tumor Growth and Anticancer Agent Efficacy.
Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes.

Mol Oncol. 2021 May 10.

Mutated circulating tumor DNA as a liquid biopsy in lung cancer detection and treatment.

Martyna Filipska, Rafael Rosell.

  Over the past decade, substantial developments have been made in the detection of circulating tumor DNA (ctDNA) - cell-free DNA (cfDNA) fragments released into the circulation from tumor cells and displaying the genetic alterations of those cells. As such, ctDNA detected in liquid biopsies serves as a powerful tool for cancer patient stratification, therapy guidance, detection of resistance and relapse monitoring. In this Review, we describe lung cancer diagnosis and monitoring strategies using ctDNA detection technologies and compile recent evidence regarding lung-cancer-related mutation detection in liquid biopsy. We focus not only on epidermal growth factor receptor (EGFR) alterations, but also on significant co-mutations that shed more light on novel ctDNA-based liquid biopsy applications. Finally, we discuss future perspectives of early cancer detection and clonal hematopoiesis filtering strategies, with possible inclusion of microbiome-driven liquid biopsy.

Keywords:  LUAD; Liquid biopsy; NSCLC; TMB; cancer detection; cfDNA; ctDNA

DOI:  https://doi.org/10.1002/1878-0261.12983
Nucleic Acids Res. 2021 May 12. pii: gkab308. [Epub ahead of print]

Cancer-causing BRCA2 missense mutations disrupt an intracellular protein assembly mechanism to disable genome maintenance.

Miyoung Lee, David Shorthouse, Robert Mahen, Benjamin A Hall, Ashok R Venkitaraman.

Cancer-causing missense mutations in the 3418 amino acid BRCA2 breast and ovarian cancer suppressor protein frequently affect a short (∼340 residue) segment in its carboxyl-terminal domain (DBD). Here, we identify a shared molecular mechanism underlying their pathogenicity. Pathogenic BRCA2 missense mutations cluster in the DBD's helical domain (HD) and OB1-fold motifs, which engage the partner protein DSS1. Pathogenic - but not benign - DBD mutations weaken or abolish DSS1-BRCA2 assembly, provoking mutant BRCA2 oligomers that are excluded from the cell nucleus, and disable DNA repair by homologous DNA recombination (HDR). DSS1 inhibits the intracellular oligomerization of wildtype, but not mutant, forms of BRCA2. Remarkably, DSS1 expression corrects defective HDR in cells bearing pathogenic BRCA2 missense mutants with weakened, but not absent, DSS1 binding. Our findings identify a DSS1-mediated intracellular protein assembly mechanism that is disrupted by cancer-causing BRCA2 missense mutations, and suggest an approach for its therapeutic correction.

DOI: https://doi.org/10.1093/nar/gkab308
Adv Exp Med Biol. 2021 ;1187 337-361

Liquid Biopsy in Breast Cancer: Circulating Tumor Cells and Circulating Tumor DNA.

Tae-Kyung Yoo.

  Cancer is associated with gene mutations, and the analysis of tumor-associated mutations is increasingly used for diagnostic, prognostic, and treatment purposes. These molecular landscapes of solid tumors are currently obtained from surgical or biopsy specimens. However, during cancer progression and treatment, selective pressures lead to additional genetic changes as tumors acquire drug resistance. Tissue sampling cannot be performed routinely owing to its invasive nature and a single biopsy only provides a limited snapshot of a tumor, which may fail to reflect spatial and temporal heterogeneity. This dilemma may be solved by analyzing cancer cells or cancer cell-derived DNA from blood samples, called liquid biopsy. Liquid biopsy is one of the most rapidly advancing fields in cancer diagnostics and recent technological advances have enabled the detection and detailed characterization of circulating tumor cells and circulating tumor DNA in blood samples.Liquid biopsy is an exciting area with rapid advances, but we are still at the starting line with many challenges to overcome. In this chapter we will explore how tumor cells and tumor-associated mutations detected in the blood can be used in the clinic. This will include detection of cancer, prediction of prognosis, monitoring systemic therapies, and stratification of patients for therapeutic targets or resistance mechanisms.

Keywords:  Breast cancer; Circulating tumor DNA; Circulating tumor cells; Liquid biopsy; Precision medicine; Tumor heterogeneity

DOI:  https://doi.org/10.1007/978-981-32-9620-6_17
Gynecol Oncol. 2021 May 05. pii: S0090-8258(21)00352-8. [Epub ahead of print]

Fragmentation of surgery and chemotherapy in the initial phase of ovarian cancer care and its association with overall survival.

Stephanie Cham, Yongmei Huang, Alexander Melamed, Michael J Worley, June Y Hou, Ana I Tergas, Fady Khoury-Collado, Allison Gockley, Caryn M S T Clair, Dawn L Hershman, Jason D Wright.

  BACKGROUND: Fragmentation occurs when a patient receives care at more than one hospital, and the long-term effects in ovarian cancer are unknown. We examined the association between fragmentation of primary debulking surgery (PDS) and adjuvant chemotherapy (AC) and overall survival (OS).METHODS: The National Cancer Database was used to identify women with stage II-IV epithelial ovarian cancer between 2004 and 2016 who underwent PDS followed by AC. Fragmentation was defined as receipt of AC at a different institution than where PDS was performed. After propensity score weighting, proportional hazard models were developed to estimate the association between fragmented care and OS.
RESULTS: Of the 36,300 patients identified, 13,347 (36.8%) had fragmented care. Patient factors associated with fragmentation included older age, higher income, and longer travel distance for PDS; hospital factors included PDS performed at a community center or a facility with lower annual surgical volume (P < 0.05, all). Fragmentation was associated with a 15% risk of 30-day delay to AC (aRR 1.15, 95% CI 1.09-1.22). In a propensity scoring weighted analysis, mortality was reduced when AC was fragmented (HR 0.95, 95% CI 0.92-0.97). Sensitivity analyses indicated fragmentation was associated with improved survival in metropolitan residents. Stratified analyses indicated patients who traveled 50 miles or more with PDS and AC at the same institution had the worst OS.
CONCLUSION: Fragmentation of PDS and AC has no adverse effects on long-term survival. Survival outcomes were worst for those who received care at the same institution 50 miles or more away.

Keywords:  Adjuvant chemotherapy; Debulking; Fragmentation; Outcomes research; Ovarian cancer

DOI:  https://doi.org/10.1016/j.ygyno.2021.04.032
Int J Gynecol Cancer. 2021 May 14. pii: ijgc-2021-002682. [Epub ahead of print]

Should we or should we not? Risk reduction bilateral salpingectomy for BRCA mutation carriers.

Vandré Cabral Gomes Carneiro, Nathalia Moreira Ramalho.



Keywords:  BRCA1 protein; BRCA2 protein; ovarian cancer

DOI:  https://doi.org/10.1136/ijgc-2021-002682
Adv Exp Med Biol. 2021 ;1187 159-179

DNA Damage Repair Inhibitor for Breast Cancer Treatment.

Ahrum Min, Kyung-Hun Lee, Seock-Ah Im.

  Cancer has been defined as a genetic disorder caused by the accumulation of genetic alterations, which result from various internal and external DNA damage that is left unrepaired. One of the main characteristics of cancer is a partial loss of DNA damage repair (DDR) pathway, resulting in increased DNA damage levels and replication stress. DDR inhibitors have been suggested as a new anticancer strategy, under the concept of synthetic lethality. The poly-(ADP-ribose) polymerase (PARP) inhibitor is the first DDR inhibitor to be used in clinical practice. PARP inhibitors have been tested in patients with BRCA1/2 germline mutations (gBRCA1/2mt) and shown robust clinical benefits in breast cancer with gBRCA1/2mt and serous ovarian cancer patients. The concept of synthetic lethality is not limited to gBRCAmt for PARP inhibitor, and discovering homologous recombination deficiency (HRD) markers beyond BRCA1/2 and identifying best candidates for DDR inhibitors are the active research areas. At the same time, various combinations of DDR inhibitors and other anticancer drugs are being tested in both preclinical and clinical studies. In addition, based on recent evidence of the immune-modulatory effect of PARP inhibitors, the combination of DDR inhibitors and immune checkpoint inhibitors is being actively investigated. Acquired resistance mechanism of DDR inhibitors, as well as defining best candidates and best combinations, would be future research topics for DDR inhibitors. Furthermore, it would also be crucial to establish a clinically relevant standardized method to detect HRD for future clinical use.

Keywords:  BRCAness; DNA damage repair; Homologous recombination deficiency; PARP inhibitor; Synthetic lethality

DOI:  https://doi.org/10.1007/978-981-32-9620-6_8
Nat Protoc. 2021 May 14.

High-throughput full-length single-cell RNA-seq automation.

Lira Mamanova, Zhichao Miao, Ayesha Jinat, Peter Ellis, Lesley Shirley, Sarah A Teichmann.

Existing protocols for full-length single-cell RNA sequencing produce libraries of high complexity (thousands of distinct genes) with outstanding sensitivity and specificity of transcript quantification. These full-length libraries have the advantage of allowing probing of transcript isoforms, are informative regarding single-nucleotide polymorphisms and allow assembly of the VDJ region of the T- and B-cell-receptor sequences. Since full-length protocols are mostly plate-based at present, they are also suited to profiling cell types where cell numbers are limiting, such as rare cell types during development. A disadvantage of these methods has been the scalability and cost of the experiments, which has limited their popularity as compared with droplet-based and nanowell approaches. Here, we describe an automated protocol for full-length single-cell RNA sequencing, including both an in-house automated Smart-seq2 protocol and a commercial kit-based workflow. The protocols take 3-5 d to complete, depending on the number of plates processed in a batch. We discuss these two protocols in terms of ease of use, equipment requirements, running time, cost per sample and sequencing quality. By benchmarking the lysis buffers, reverse transcription enzymes and their combinations, we have optimized the in-house automated protocol to dramatically reduce its cost. An automated setup can be adopted easily by a competent researcher with basic laboratory skills and no prior automation experience. These pipelines have been employed successfully for several research projects allied with the Human Cell Atlas initiative ( www.humancellatlas.org ).

DOI: https://doi.org/10.1038/s41596-021-00523-3
Mol Cell. 2021 May 04. pii: S1097-2765(21)00328-2. [Epub ahead of print]

The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target.

Michael F Sharp, Rohan Bythell-Douglas, Andrew J Deans, Wayne Crismani.

Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical-and likely singular-role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous DNA damage, including cells that lack BRCA1, BRCA2, ATM, or functionally related genes. In this perspective, we discuss the genetic and biochemical evidence in support of the FA core complex as a compelling drug target for cancer therapy. In particular, we discuss the genetic, biochemical, and structural data that could rapidly advance our capacity to identify and implement the use of FA core complex inhibitors in the clinic.

DOI: https://doi.org/10.1016/j.molcel.2021.04.023
BMC Cancer. 2021 May 08. 21(1): 525

Comparison of dose-dense vs. 3-weekly paclitaxel and carboplatin in the first-line treatment of ovarian cancer in a propensity score-matched cohort.

Rafaela Pirolli, Viviane Teixeira Loiola de Alencar, Felipe Leonardo Estati, Adriana Regina Gonçalves Ribeiro, Daniella Yumi Tsuji Honda, Mariana de Oliveira, Joao Paulo da Silveira Nogueira Lima, Elizabeth Santana Dos Santos, Andrea Paiva Gadelha Guimarães, Glauco Baiocchi, Alexandre André Balieiro Anastácio da Costa.

  BACKGROUND: Benefit of carboplatin and dose-dense weekly paclitaxel (ddCT) in first line treatment of ovarian cancer patients has been different in Western and Asian studies. In the present study we compare progression-free survival (PFS) of ddCT to three-weekly carboplatin and paclitaxel (CT) in first-line treatment of ovarian carcinoma in a single institution in a Western population.MATERIALS AND METHODS: We conducted a retrospective review of medical records from patients with ovarian carcinoma treated in a tertiary cancer center from 2007 to 2018. All patients treated with ddCT or CT in the first-line setting were included. Patients who received first-line bevacizumab were not included. PFS and overall survival (OS) were compared in a propensity score-matched cohort to address selection bias. Patients were matched according to age, ECOG performance status, CA 125, FIGO stage, residual disease, and histological subtype, in a 1:2 ratio.
RESULTS: Five hundred eighty-eight patients were eligible for propensity score matching, the final cohort consisted of 69 patients treated with ddCT and 138 CT group. Baseline characteristics were well-balanced. After a median follow-up of 65.1 months, median PFS was 29.3 vs 20.0 months, favouring ddCT treatment (p = 0.035). In the multivariate cox regression ddCT showed a 18% lower risk of progression (HR 0.82, 95% CI 0.68-0.99, p = 0.04). Overall survival data is immature, but suggested better outcomes for ddCT (not reached versus 78.8 months; p = 0.07).
CONCLUSION: Our retrospective study has shown superior PFS of ddCT over CT regimen in first-line treatment of ovarian carcinoma in a Western population not treated with bevacizumab.

Keywords:  Carboplatin; Chemotherapy; Dose-dense; Ovarian cancer; Weekly paclitaxel

DOI:  https://doi.org/10.1186/s12885-021-08270-0
J Gastrointest Oncol. 2021 Apr;12(Suppl 1): S137-S143

Narrative review of cytoreductive surgery and intraperitoneal chemotherapy for peritoneal metastases in ovarian cancer.

Thomas Boerner, Oliver Zivanovic, Dennis S Chi.

  Due to numerous factors, such as no specific symptoms and ineffective screening to identify premalignant or early-stage disease, most patients with ovarian cancer present with advanced-stage disease and overt peritoneal metastases. Currently, the most effective treatment for these patients is complete cytoreductive surgery with systemic platinum/taxane-based chemotherapy. Over the past few decades, many researchers have evaluated the use of postoperative normothermic intraperitoneal (NIPEC) and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) delivery as additional treatment modalities. Here, we will review the current status and future directions for these treatment strategies in the management of ovarian cancer. Most of the studies in this area of research have been retrospective in nature, limited by heterogeneous patient populations and large variance in chemotherapeutic regimens used, leading to mixed results and difficulties in evaluating the clinical impact of the data. More mature data from prospective trials are lacking, and IP therapy for advanced ovarian cancer should still be considered an investigational approach and evaluated only in clinical trials; the exception is for patients with stage III disease who undergo interval debulking surgery after neoadjuvant chemotherapy, for whom HIPEC can be considered in selected patients as part of first-line therapy.

Keywords:  Intraperitoneal chemotherapy; cytoreductive surgery; hyperthermic intraperitoneal chemotherapy; ovarian cancer; peritoneal metastases

DOI:  https://doi.org/10.21037/jgo-20-274
BMJ. 2021 May 12. 373 n1223

Screening for ovarian cancer is ruled out after trial found it did not reduce deaths.

Nikki Nabavi.

DOI: https://doi.org/10.1136/bmj.n1223
J Obstet Gynaecol Res. 2021 May 10.

Application of artificial intelligence in gynecologic malignancies: A review.

Kenbun Sone, Yusuke Toyohara, Ayumi Taguchi, Yuichiro Miyamoto, Michihiro Tanikawa, Mayuyo Uchino-Mori, Takayuki Iriyama, Tetsushi Tsuruga, Yutaka Osuga.

  With the development of machine learning and deep learning models, artificial intelligence is now being applied to the field of medicine. In oncology, the use of artificial intelligence for the diagnostic evaluation of medical images such as radiographic images, omics analysis using genome data, and clinical information has been increasing in recent years. There have been increasing numbers of reports on the use of artificial intelligence in the field of gynecologic malignancies, and we introduce and review these studies. For cervical and endometrial cancers, the evaluation of medical images, such as colposcopy, hysteroscopy, and magnetic resonance images, using artificial intelligence is frequently reported. In ovarian cancer, many reports combine the assessment of medical images with the multi-omics analysis of clinical and genomic data using artificial intelligence. However, few study results can be implemented in clinical practice, and further research is needed in the future.

Keywords:  artificial intelligence; deep learning; gynecological malignancies; machine learning; neural network

DOI:  https://doi.org/10.1111/jog.14818
Br J Cancer. 2021 May 12.

Targeting the actin/tropomyosin cytoskeleton in epithelial ovarian cancer reveals multiple mechanisms of synergy with anti-microtubule agents.

Xing Xu, Yao Wang, Nicole S Bryce, Katrina Tang, Nicola S Meagher, Eun Young Kang, Linda E Kelemen, Martin Köbel, Susan J Ramus, Michael Friedlander, Caroline E Ford, Edna C Hardeman, Peter W Gunning.

BACKGROUND: Anti-microtubule agents are widely used to treat ovarian cancers, but the efficacy is often compromised by drug resistance. We investigated co-targeting the actin/tropomyosin cytoskeleton and microtubules to increase treatment efficacy in ovarian cancers and potentially overcome resistance.METHODS: The presence of tropomyosin-3.1 (Tpm3.1) was examined in clinical specimens from ovarian cancer patients using immunohistochemistry. Combinatorial effects of an anti-Tpm3.1 compound, ATM-3507, with vinorelbine and paclitaxel were evaluated in ovarian cancer cells via MTS and apoptosis assays. The mechanisms of action were established using live- and fixed-cell imaging and protein analysis.
RESULTS: Tpm3.1 is overexpressed in 97% of tumour tissues (558 of 577) representing all histotypes of epithelial ovarian cancer. ATM-3507 displayed synergy with both anti-microtubule agents to reduce cell viability. Only vinorelbine synergised with ATM-3507 in causing apoptosis. ATM-3507 significantly prolonged vinorelbine-induced mitotic arrest with elevated activity of the spindle assembly checkpoint and mitotic cell death; however, ATM-3507 showed minor impact on paclitaxel-induced mitotic defects. Both combinations substantially increased post-mitotic G1 arrest with cyclin D1 and E1 downregulation and an increase of p21Cip and p27Kip.
CONCLUSION: Combined targeting of Tpm3.1/actin and microtubules is a promising treatment strategy for ovarian cancer that should be further tested in clinical settings.

DOI: https://doi.org/10.1038/s41416-021-01420-y
Ann Transl Med. 2021 Apr;9(8): 645

Inhibition of sphingosine kinase 2 down-regulates ERK/c-Myc pathway and reduces cell proliferation in human epithelial ovarian cancer.

Lan Dai, Wenjing Wang, Yixuan Liu, Keqi Song, Wen Di.

  Background: Epithelial ovarian cancer (EOC) is the leading cause of death from female cancers. In our previous study, sphingosine kinase 2 (SphK2) inhibitor was shown to display anti-EOC activities. The purpose of this study was to evaluate further the expression characteristics and clinical significance of SphK2 in EOC and to explore the roles and underlying mechanisms of SphK2 in EOC cell survival.Methods: The expression of SphK2 was examined by immunohistochemistry (IHC) and Western blot, and its clinical implications and prognostic significance were analyzed. We performed a cellular proliferation assay, and a mouse xenograft model was established to confirm the roles of SphK2 in vitro and in vivo. Cell cycle analysis, apoptosis assay, and Western blot were performed to examine cell cycle progression and apoptosis rate. Gene set enrichment analysis (GSEA), and Western blot were used to investigate the downstream signaling pathways related to SphK2 function.
Results: The expression level of SphK2 was shown to be associated with stage, histological grade, lymph node metastasis, and ascites status. More importantly, a high SphK2 expression level was a prognostic indicator of overall survival (OS) and relapse-free survival (RFS). Moreover, knockdown of SphK2 arrested cell cycle progression and inhibited EOC cell proliferation both in vitro and in vivo. Furthermore, ERK/c-Myc, the key pathway in EOC progression, was important for SphK2-mediated mitogenic action in EOC cells.
Conclusions: Our findings provided the first evidence that SphK2 played a crucial role in EOC proliferation by regulating the ERK/c-Myc pathway. This indicated that SphK2 might serve as a prognostic marker and potential therapeutic target in EOC.

Keywords:  Epithelial ovarian cancer (EOC); c-Myc; extracellular signal-regulated kinase (ERK); proliferation; sphingosine kinase 2 (SphK2)

DOI:  https://doi.org/10.21037/atm-20-6742
Insights Imaging. 2021 May 11. 12(1): 60

Low-grade serous epithelial ovarian cancer: a comprehensive review and update for radiologists.

Sofia Amante, Filipa Santos, Teresa Margarida Cunha.

  Low-grade serous carcinoma (LGSC) is an infrequent subtype of ovarian cancer, corresponding to 5% of epithelial neoplasms. This subtype of ovarian carcinoma characteristically has molecular features, pathogenesis, clinical behaviour, sensitivity to chemotherapy, and prognosis distinct to high-grade serous carcinoma (HGSC). Knowing the difference between LGSC and other ovarian serous tumours is vital to guide clinical management, which currently is only possible histologically. However, imaging can provide several clues that allow differentiating LGSC from other tumours and enable precise staging and follow-up of ovarian cancer treatment. Characteristically, LGSC appears as mixed lesions with variable papillary projections and solid components, usually in different proportions from those detected in serous borderline tumour and HGSC. Calcified extracellular bodies, known as psammoma bodies, are also a common feature of LGSC, frequently detectable within lymphadenopathies and metastases associated with this type of tumour. In addition, the characterisation of magnetic resonance imaging enhancement also plays an essential role in calculating the probability of malignancy of these lesions. As such, in this review, we discuss and update the distinct radiological modalities features and the clinicopathologic characteristics of LGSC to allow radiologists to be familiarised with them and to narrow the differential diagnosis when facing this type of tumour.

Keywords:  Computed tomography; Epithelial ovarian carcinoma; Imaging; Low-grade serous carcinoma; Magnetic resonance imaging

DOI:  https://doi.org/10.1186/s13244-021-01004-7
FEBS J. 2021 May 13.

Therapeutic targeting of chromatin: Status and opportunities.

Marton Siklos, Stefan Kubicek.

  The molecular characterization of mechanisms underlying transcriptional control and epigenetic inheritance since the 1990s has paved the way for the development of targeted therapies that modulate these pathways. In the past two decades, cancer genome sequencing approaches have uncovered a plethora of mutations in chromatin modifying enzymes across tumor types, and systematic genetic screens have identified many of these proteins as specific vulnerabilities in certain cancers. Now is the time when many of these basic and translational efforts start to bear fruit and more and more chromatin-targeting drugs are entering the clinic. At the same time, novel pharmacological approaches harbor the potential to modulate chromatin in unprecedented fashion, thus generating entirely novel opportunities. Here we review the current status of chromatin targets in oncology and describe a vision for the epigenome-modulating drugs of the future.

Keywords:  BET; BRD4; Chromatin; DNMT; DOT1L; EZH2; HDAC; LSD1; PROTAC; cancer; degrader; epigenetics; erasers; metabolic enzymes; molecular glue; readers; writers

DOI:  https://doi.org/10.1111/febs.15966
Int J Gynecol Cancer. 2021 May 14. pii: ijgc-2020-002343. [Epub ahead of print]

Cytoreductive surgery followed by chemotherapy and olaparib maintenance in BRCA 1/2 mutated recurrent ovarian cancer: a retrospective MITO group study.

Sabrina Chiara Cecere, Lucia Musacchio, Michele Bartoletti, Vanda Salutari, Laura Arenare, Domenica Lorusso, Graziana Ronzino, Rossella Lauria, Gennaro Cormio, Emanuele Naglieri, Paolo Scollo, Claudia Marchetti, Francesco Raspagliesi, Stefano Greggi, Saverio Cinieri, Alice Bergamini, Michele Orditura, Giorgio Valabrega, Giovanni Scambia, Fabio Martinelli, Elisabetta De Matteis, Cinzia Cardalesi, Vera Loizzi, Giorgia Perniola, Claudia Carella, Giuseppa Scandurra, Gaia Giannone, Sandro Pignata.

  INTRODUCTION: The role of cytoreductive surgery in the poly-ADP ribose polymerase inhibitors era is not fully investigated. We evaluated the impact of surgery performed prior to platinum-based chemotherapy followed by olaparib maintenance in platinum-sensitive BRCA-mutated recurrent ovarian cancer.METHODS: This retrospective study included platinum-sensitive recurrent ovarian cancer BRCA-mutated patients from 13 Multicenter Italian Trials in Ovarian cancer and gynecological malignancies centers treated between September 2015 and May 2019. The primary outcomes were progression-free survival and overall survival. Data on post-progression treatment was also assessed.
RESULTS: Among 209 patients, 72 patients (34.5%) underwent cytoreductive surgery followed by platinum-based chemotherapy and olaparib maintenance, while 137 patients (65.5%) underwent chemotherapy treatment alone. After a median follow-up of 37.3 months (95% CI: 33.4 to 40.8), median progression-free survival in the surgery group was not reached, compared with 11 months in patients receiving chemotherapy alone (P<0.001). Median overall survival was nearly double in patients undergoing surgery before chemotherapy (55 vs 28 months, P<0.001). Post-progression therapy was assessed in 127 patients: response rate to chemotherapy was 29.2%, 8.8%, and 9.0% in patients with platinum-free interval >12 months, between 6 and 12 months, and <6 months, respectively.
CONCLUSION: Cytoreductive surgery performed before platinum therapy and olaparib maintenance was associated with longer progression-free survival and overall survival in BRCA-mutated platinum-sensitive relapsed ovarian cancer patients. In accordance with our preliminary results, the response rate to chemotherapy given after progression during olaparib was associated with platinum-free interval.

Keywords:  cytoreduction surgical procedures; ovarian cancer

DOI:  https://doi.org/10.1136/ijgc-2020-002343
J Clin Oncol. 2021 May 10. JCO2100003

Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2.

Kim A Reiss, Rosemarie Mick, Mark H O'Hara, Ursina Teitelbaum, Thomas B Karasic, Charles Schneider, Stacy Cowden, Traci Southwell, Janae Romeo, Natallia Izgur, Zain M Hannan, Rashmi Tondon, Katherine Nathanson, Robert H Vonderheide, Max M Wattenberg, Gregory Beatty, Susan M Domchek.

PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline BRCA1 or BRCA2 pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in BRCA1, BRCA2, or PALB2.PATIENTS AND METHODS: Eligible patients had advanced PC; germline (g) or somatic (s) PVs in BRCA1, BRCA2, or PALB2, and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival.
RESULTS: Of 46 enrolled patients, 42 were evaluable (27 gBRCA2, seven gBRCA1, six gPALB2, and two sBRCA2). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with gBRCA2 (41%, 11 out of 27), gPALB2 (50%, 3 out of 6), and sBRCA2 (50%, 1 out of 2). No new safety signals were noted.
CONCLUSION: Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in BRCA1, BRCA2, or PALB2. The finding of efficacy in patients with gPALB2 and sBRCA2 PVs expands the population likely to benefit from PARPi beyond gBRCA1/2 PV carriers.

DOI: https://doi.org/10.1200/JCO.21.00003
Mol Cells. 2021 04 23.

The Role of Gut Microbiota in Modulating Tumor Growth and Anticancer Agent Efficacy.

Jaeho Kim, Heung Kyu Lee.

  An increasing number of studies have revealed an interaction between gut microbiota and tumors. The enrichment of specific bacteria strains in the intestines has been found to modulate tumor growth and influence the mechanisms of tumor treatment. Various bacteria are involved in modulating the effects of chemotherapeutic drugs currently used to treat patients with cancer, and they affect not only gastrointestinal tract tumors but also distant organ tumors. In addition, changes in the gut microbiota are known to be involved in the antitumor immune response as well as the modulation of the intestinal immune system. As a result, the gut microbiota plays an important role in modulating the efficacy of immune checkpoint inhibitors. Therefore, gut microbiota could be considered as an adjuvant treatment option with other cancer treatment or as another marker for predicting treatment response. In this review, we examine how gut microbiota affects cancer treatments.

Keywords:  cancer; cancer therapy; gut microbiota; immune checkpoint inhibitors

DOI:  https://doi.org/10.14348/molcells.2021.0032
Front Immunol. 2021 ;12 660560

Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes.

Clara Taffoni, Alizée Steer, Johanna Marines, Hanane Chamma, Isabelle K Vila, Nadine Laguette.

  The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

Keywords:  DNA damage responses; DNA-PK; IFI16; cGAS-STING; cytosolic nucleic acids; inflammation; tumorigenesis

DOI:  https://doi.org/10.3389/fimmu.2021.660560