Estimation of risk posed by malignant polyps amongst colorectal surgeons in Australia and New Zealand.

PURPOSE: The estimation of the risk posed by malignant polyps for residual or lymphatic disease plays a central role. This study investigated colorectal surgeons' assessment of these risks associated with malignant polyps. METHODS: A cross-sectional questionnaire was electronically administered to colorectal surgeons in Australia and New Zealand in October 2022. The questionnaire contained 17 questions on demographics, when surgeons consider colorectal resection appropriate, and the risk assessment for 5 hypothetical malignant polyps. RESULTS: The mean risk of residual or lymphatic disease that would prompt surgeons to recommend colonic resection was 5%. However, this increased to a mean risk of 10% if the malignant polyp was located in the rectum, and the only resection option was abdominoperineal resection with end-colostomy. There was high concordance between the estimated risk of residual or lymphatic disease by colorectal surgeons and the Association of Coloproctology of Great Britain and Ireland (ACPGBI) guidelines for the 5 hypothetical malignant polyps, with the ACPGBI estimated risk lying within the 95% confidence interval for 4 of the 5 malignant polyps. Nonetheless, 96.6% of surgeons felt that an online risk calculator would improve clinical practice. CONCLUSION: Colorectal surgeons in Australia and New Zealand accurately estimated the risk posed by malignant polyps. An online risk calculator may assist in better conveying risk to patients.

Inhibition of Aurora B kinase (AURKB) enhances the effectiveness of 5-fluorouracil chemotherapy against colorectal cancer cells.

BACKGROUND: 5-Fluorouracil (5-FU) remains a core component of systemic therapy for colorectal cancer (CRC). However, response rates remain low, and development of therapy resistance is a primary issue. Combinatorial strategies employing a second agent to augment the therapeutic effect of chemotherapy is predicted to reduce the incidence of treatment resistance and increase the durability of response to therapy. METHODS: Here, we employed quantitative proteomics approaches to identify novel druggable proteins and molecular pathways that are deregulated in response to 5-FU, which might serve as targets to improve sensitivity to chemotherapy. Drug combinations were evaluated using 2D and 3D CRC cell line models and an ex vivo culture model of a patient-derived tumour. RESULTS: Quantitative proteomics identified upregulation of the mitosis-associated protein Aurora B (AURKB), within a network of upregulated proteins, in response to a 24 h 5-FU treatment. In CRC cell lines, AURKB inhibition with the dihydrogen phosphate prodrug AZD1152, markedly improved the potency of 5-FU in 2D and 3D in vitro CRC models. Sequential treatment with 5-FU then AZD1152 also enhanced the response of a patient-derived CRC cells to 5-FU in ex vivo cultures. CONCLUSIONS: AURKB inhibition may be a rational approach to augment the effectiveness of 5-FU chemotherapy in CRC.

UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). METHODS: Immunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined. RESULTS: High UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. High UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH high TIC population. Conversely, overexpression of UGDH in the C4/Differentiated subtype reduced the TIC population. In co-culture models, UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins, and fibroblast collagen production. Inflammatory cytokine expression of spheroids was altered by UGDH expression. The effect of UGDH knockdown or overexpression in the C1/ Mesenchymal and C4/Differentiated subtypes respectively was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH improved survival and reduced tumor burden in C1/Mesenchymal compared to controls. CONCLUSIONS: These data show that modulation of UGDH expression in ovarian cancer reveals distinct roles for UGDH in the C1/Mesenchymal and C4/Differentiated molecular subtypes of EOC, influencing the tumor microenvironmental composition. UGDH is a strong potential therapeutic target in TICs, for the treatment of EOC, particularly in patients with the mesenchymal molecular subtype.

MUC13 Cell Surface Mucin Limits Salmonella Typhimurium Infection by Protecting the Mucosal Epithelial Barrier.

BACKGROUND & AIMS: MUC13 cell surface mucin is highly expressed on the mucosal surface throughout the intestine, yet its role against bacterial infection is unknown. We investigated how MUC13 impacts Salmonella typhimurium (S Tm) infection and elucidated its mechanisms of action. METHODS: Muc13-/- and wild-type littermate mice were gavaged with 2 isogenic strains of S Tm after pre-conditioning with streptomycin. We assessed clinical parameters, cecal histology, local and systemic bacterial load, and proinflammatory cytokines after infection. Cecal enteroids and epithelial cell lines were used to evaluate the mechanism of MUC13 activity after infection. The interaction between bacterial SiiE and MUC13 was assessed by using siiE-deficient Salmonella. RESULTS: S Tm-infected Muc13-/- mice had increased disease activity, histologic damage, and higher local and systemic bacterial loads. Mechanistically, we found that S Tm binds to MUC13 through its giant SiiE adhesin and that MUC13 acts as a pathogen-binding decoy shed from the epithelial cell surface after pathogen engagement, limiting bacterial invasion. In addition, MUC13 reduces epithelial cell death and intestinal barrier breakdown by enhancing nuclear factor kappa B signaling during infection, independent of its decoy function. CONCLUSIONS: We show for the first time that MUC13 plays a critical role in antimicrobial defense against pathogenic S Tm at the intestinal mucosal surface by both acting as a releasable decoy limiting bacterial invasion and reducing pathogen-induced cell death. This further implicates the cell surface mucin family in mucosal defense from bacterial infection.

First records of Hamacantha species from seamounts off eastern Australia (Porifera, Demospongiae, Merliida), with description of four new species.

Four new species of encrusting Hamacantha (Vomerula) are described from bathyal depths of seamounts off Queensland and Tasmania in southeast Australia (H. (V.) novacula sp. nov., H. (V.) melliflura sp. nov., H. (V.) ridleyi sp. nov., H. (V.) levii sp. nov.). A previously described species known only from New Caledonia (H. (V.) acerata Lévi, 1993) has also been redescribed. A tabular comparison of all known species of H. (Vomerula) is provided, bringing the number of known species in the subgenus to 26. This is also the first record of the genus Hamacantha from the Australian Exclusive Economic Zone.

New carnivorous sponges from the Great Barrier Reef, Queensland, Australia collected by ROV from the RV FALKOR.

This research presents three new species of carnivorous sponges from the family Cladorhizidae from the Great Barrier Reef, in Queensland, Australia: Abyssocladia falkor sp. nov., Abyssocladia jeanvaceleti sp. nov. and Axoniderma wanda sp. nov. They were collected by ROV during the expedition FK200802-Seamounts, Canyons & Reefs of the Coral Sea Cruise on the RV Falkor from the Schmidt Ocean Institute. In addition, the ROV collection of two complete specimens enabled the redescription of two other Australian species of carnivorous sponge (Chondrocladia (Chondrocladia) zygainadentonis Ekins et al., 2020a and Asbestopluma (Asbestopluma) maxisigma Ekins et al., 2020a), previously known from the East coast of Australia based on incomplete specimens.

Improved concordance of challenging human epidermal growth factor receptor 2 dual in-situ hybridisation cases with the use of a digital image analysis algorithm in breast cancer.

AIMS: Accurate assessment of human epidermal growth factor receptor 2 (HER2) expression by HER2 immunohistochemistry and in-situ hybridisation (ISH) is critical for the management of patients with breast cancer. The revised 2018 ASCO/CAP guidelines define 5 groups based on HER2 expression and copy number. Manual pathologist quantification by light microscopy of equivocal and less common HER2 ISH groups (groups 2-4) can be challenging, and there are no data on interobserver variability in reporting of these cases. We sought to determine whether a digital algorithm could improve interobserver variability in the assessment of difficult HER2 ISH cases. METHODS AND RESULTS: HER2 ISH was evaluated in a cohort enriched for less common HER2 patterns using standard light microscopy versus analysis of whole slide images using the Roche uPath HER2 dual ISH image analysis algorithm. Standard microscopy demonstrated significant interobserver variability with a Fleiss's kappa value of 0.471 (fair-moderate agreement) improving to 0.666 (moderate-good) with the use of the algorithm. For HER2 group designation (groups 1-5), there was poor-moderate reliability between pathologists by microscopy [intraclass correlation coefficient (ICC) = 0.526], improving to moderate-good agreement (ICC = 0.763) with the use of the algorithm. In subgroup analysis, the algorithm improved concordance particularly in groups 2, 4 and 5. Time to enumerate cases was also significantly reduced. CONCLUSION: This work demonstrates the potential of a digital image analysis algorithm to improve the concordance of pathologist HER2 amplification status reporting in less common HER2 groups. This has the potential to improve therapy selection and outcomes for patients with HER2-low and borderline HER2-amplified breast cancers.

Discovery and validation of serum glycoprotein biomarkers for high grade serous ovarian cancer.

PURPOSE: This study aimed to identify serum glycoprotein biomarkers for early detection of high-grade serous ovarian cancer (HGSOC), the most common and aggressive histotype of ovarian cancer. EXPERIMENTAL DESIGN: The glycoproteomics pipeline lectin magnetic bead array (LeMBA)-mass spectrometry (MS) was used in age-matched case-control serum samples. Clinical samples collected at diagnosis were divided into discovery (n = 30) and validation (n = 98) sets. We also analysed a set of preclinical sera (n = 30) collected prior to HGSOC diagnosis in the UK Collaborative Trial of Ovarian Cancer Screening. RESULTS: A 7-lectin LeMBA-MS/MS discovery screen shortlisted 59 candidate proteins and three lectins. Validation analysis using 3-lectin LeMBA-multiple reaction monitoring (MRM) confirmed elevated A1AT, AACT, CO9, HPT and ITIH3 and reduced A2MG, ALS, IBP3 and PON1 glycoforms in HGSOC. The best performing multimarker signature had 87.7% area under the receiver operating curve, 90.7% specificity and 70.4% sensitivity for distinguishing HGSOC from benign and healthy groups. In the preclinical set, CO9, ITIH3 and A2MG glycoforms were altered in samples collected 11.1 ± 5.1 months prior to HGSOC diagnosis, suggesting potential for early detection. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings provide evidence of candidate early HGSOC serum glycoprotein biomarkers, laying the foundation for further study in larger cohorts.

Reactive Oxygen Species as Mediators of Disease Progression and Therapeutic Response in Colorectal Cancer.

Significance: Reactive oxygen species (ROS) are critical to normal cellular function with redox homeostasis achieved by balancing ROS production with removal through detoxification mechanisms. Many of the conventional chemotherapies used to treat colorectal cancer (CRC) derive a proportion of their cytotoxicity from ROS generation, and resistance to chemotherapy is associated with elevated detoxification mechanisms. Furthermore, cancer stem cells demonstrate elevated detoxification mechanisms making definitive treatment with existing chemotherapy challenging. In this article, we review the roles of ROS in normal and malignant colonic cell biology and how existing and emerging therapies might harness ROS for therapeutic benefit. Recent Advances: Recent publications have elucidated the contribution of ROS to the cytotoxicity of conventional chemotherapy alongside the emerging approaches of photodynamic therapy (PDT), sonodynamic therapy (SDT), and radiodynamic therapy (RDT), in which ROS are generated in response to excitatory light, sound, or X-ray stimuli to promote cancer cell apoptosis. Critical Issues: The majority of patients with metastatic CRC have a very poor prognosis with a 5-year survival of ∼13% making the need for new or more effective treatments an imperative. Future Directions: Modulation of ROS through a combination of new and emerging therapies may improve the efficacy of current chemotherapy providing novel approaches to treat the otherwise resistant disease. Antioxid. Redox Signal. 39, 186-205.

Malignant polyps in the COVID-19 era: a population-based analysis.

BACKGROUND: Malignant polyps represent the early development of colorectal adenocarcinoma. During 2020, there was widescale rationing of health-care resources in response to the COVID-19 pandemic. In particular there was deferral of some colonoscopy procedures required for timely malignant polyp detection. This study sought to assess how these deferrals affected the diagnosis of malignant polyps. METHODS: A population wide analysis was performed of 2079 malignant polyps, diagnosed in Queensland, Australia from 2011 to 2020. A regression analysis, with 95% prediction intervals, was produced to determine whether there was a significant impact on the number of malignant polyps diagnosed in 2020 compared to previous years. Univariate statistical analysis of patient, procedural, and pathological variables was also performed. RESULTS: In 2020 there were 211 malignant polyps diagnosed, which was significantly lower than was predicted by the univariate regression analysis (r2  = 0.85, 95% prediction interval: 255.07-323.91, P < 0.001). These malignant polyps were less likely to be diagnosed in a private setting (P < 0.001), and exhibited significantly less depth of submucosal invasion (P = 0.017). There was no significant difference in the management strategy (polypectomy, resection or trans-anal resection) between 2011 and 2019 and 2020. CONCLUSION: Because of the significant decrease in the number of malignant polyps, and the natural history of the disease, it is expected that there will be an increase in more advanced colorectal adenocarcinomas presenting in 2021 and beyond. This has implications for healthcare resources, particularly in light of the ongoing strain on health departments as a result of the COVID-19 pandemic.

The roles of proteases in prostate cancer.

Since the proposition of the pro-invasive activity of proteolytic enzymes over 70 years ago, several roles for proteases in cancer progression have been established. About half of the 473 active human proteases are expressed in the prostate and many of the most well-characterized members of this enzyme family are regulated by androgens, hormones essential for development of prostate cancer. Most notably, several kallikrein-related peptidases, including KLK3 (prostate-specific antigen, PSA), the most well-known prostate cancer marker, and type II transmembrane serine proteases, such as TMPRSS2 and matriptase, have been extensively studied and found to promote prostate cancer progression. Recent findings also suggest a critical role for proteases in the development of advanced and aggressive castration-resistant prostate cancer (CRPC). Perhaps the most intriguing evidence for this role comes from studies showing that the protease-activated transmembrane proteins, Notch and CDCP1, are associated with the development of CRPC. Here, we review the roles of proteases in prostate cancer, with a special focus on their regulation by androgens.

In comparison with polypectomy, colorectal resection is associated with improved survival for patients diagnosed with malignant polyps.

AIM: Patients diagnosed with a malignant polyp generally have favourable overall survival (OS) and cancer-specific survival (CSS). However, it is unclear how choice in management for malignant polyps may affect survival. METHODS: Data from the Queensland Oncology Repository was analysed to derive a population wide assessment of the impact of management strategy on OS and CSS for patients diagnosed with malignant polyps. Log-rank testing, Kaplan-Meier and Cox-regression models were performed. Patients were matched using propensity score and Mahalanobis distance matching. RESULTS: A total of 1,646 patients were included with 240 deaths and 52 colorectal cancer related deaths until censor date. Following propensity score and Mahalanobis distance matching of patients undergoing polypectomy alone versus colorectal resection, there was no significant difference in the age groups (<60 years of age or ≥60 years of age), American Society of Anesthesiology score, comorbidity count or Association of ColoProctology of Great Britain and Ireland risk category. However, of note Log-rank testing demonstrated a significant difference in OS (p < 0.001) and CSS (p = 0.0061) between management strategies. Multivariable Cox-regression models in matched and un-matched patient cohorts demonstrated significantly lower hazards of death for OS with resection (p < 0.001). However, CSS was no longer significantly different between management groups in multivariable Cox-regression analysis (p = 0.073). CONCLUSION: Patients who underwent colorectal resection had significantly improved OS and CSS compared with polypectomy alone. Improved OS was furthermore seen on multivariable analysis, and in matched cohorts. Future research should investigate why this unexpected finding may be the case and whether updates to guidelines should be considered.

Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-tumor activity in MYC-high high-grade serous ovarian carcinoma.

Approximately 50%-55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. Because MYC is not directly targetable, we have analyzed molecular pathways enriched in MYC-high HGSOC tumors to identify potential therapeutic targets. Here, we report that MYC-high HGSOC tumors show enrichment in genes controlled by NRF2, an antioxidant signaling pathway, along with increased thioredoxin redox activity. Treatment of MYC-high HGSOC tumors cells with US Food and Drug Administration (FDA)-approved thioredoxin reductase 1 (TrxR1) inhibitor auranofin resulted in significant growth suppression and apoptosis in MYC-high HGSOC cells in vitro and also significantly reduced tumor growth in an MYC-high HGSOC patient-derived tumor xenograft. We found that auranofin treatment inhibited glycolysis in MYC-high cells via oxidation-induced GAPDH inhibition. Interestingly, in response to auranofin-induced glycolysis inhibition, MYC-high HGSOC cells switched to glutamine metabolism for survival. Depletion of glutamine with either glutamine starvation or glutaminase (GLS1) inhibitor CB-839 exerted synergistic anti-tumor activity with auranofin in HGSOC cells and OVCAR-8 cell line xenograft. These findings suggest that applying a combined therapy of GLS1 inhibitor and TrxR1 inhibitor could effectively treat MYC-high HGSOC patients.

Management of high and low risk malignant polyps: a population-wide analysis.

AIM: The management of malignant polyps is a treatment dilemma in selecting between polypectomy and colorectal resection. To assist clinicians, guidelines have been developed by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) to provide treatment recommendations. METHODS: This study compared management strategy based on the ACPGBI risk categorization for malignant polyps. Univariable and multivariable statistical analysis was undertaken to assess the factors predicting management strategy. A population-wide analysis was performed of 1646 malignant polyps and the factors that predicted their management strategy, from Queensland, Australia, from 2011 to 2019. RESULTS: Overall, 31.55% of patients with very low or low risk disease proceeded to resection. Of those with high or very high risk disease, 36.69% did not proceed to resection. In very low and low risk polyps, age (P = 0.003) and polyp location (P < 0.001) were significantly different between the colorectal resection group and the polypectomy alone group. In those with very high or high risk polyps age (P < 0.001), type of facility (public or private) for the colonoscopy (P = 0.037), right colonic polyps compared to left colonic polyps (P = 0.015) and rectal polyps (P < 0.001) and mismatch repair mutations present (P = 0.027) were predictive of resection in high risk disease using a multivariable model. CONCLUSION: Over 30% of patients with very low and low risk malignant polyps proceeded to resection, against the advice of guidelines. Furthermore, over 35% of patients with very high or high risk malignant polyps did not proceed to resection. Education strategies may improve management decision choices. Furthermore, improvements in data collation will improve the understanding of management choices in the future.

Missing parameters in malignant polyp histology reports: can appropriate decisions be made?

The treatment of colorectal malignant polyps is dependent upon quality reporting of the histopathological features known to predict the risk of residual disease or lymph node metastasis. The Royal College of Pathologists of Australasia (RCPA) has produced protocols covering mandatory and recommended pathological parameters to be included in the pathology reporting of malignant polyps. This paper aimed to assess the quality of the pathological reporting in a population-wide analysis from 2011-2019 in Queensland, Australia. A retrospective population-wide cohort study was performed using the Queensland Oncology Repository as a data source. The number of missing pathological parameters (assessed against the RCPA protocol standards and guidelines) for each patient was then summed. Demographic and other patient details were collated. The number of patients whose recommended treatment could theoretically be altered by the full reporting of missing parameters was calculated. A total of 1,646 histopathological reports of malignant polyps were reviewed. From this, 30.8% of all reports had a sufficient number of missing parameters that may have seen an alternate management strategy chosen. The most commonly under-reported parameter from the standards was either a Haggitt or Kikuchi level with 48.6% missing. Synoptic reporting significantly reduced the mean number of missing pathological parameters (p<0.001) There was a significant improvement in the number of missing pathological details over time (p<0.001). Accurate and complete pathology reports are essential to formulate appropriate surgical recommendations after the resection of malignant polyps. In this population-based study, pathology reports remain incomplete for the established parameters despite the introduction of an RCPA structured reporting protocol. Fortunately, the quality of pathological reporting has improved since the introduction of the first RCPA protocol covering reporting of malignant polyps.

Timing of surveillance colonoscopy following malignant colorectal polypectomy in Queensland.

INTRODUCTION: The management of malignant polyps presents a treatment challenge between a colorectal resection and polypectomy alone. Patients managed with polypectomy alone typically undergo surveillance for recurrent or metastatic disease, however, optimal timing of surveillance methods remains unclear. Guidelines recommend for completely resected malignant polyps, that a surveillance colonoscopy be perform 12 months from diagnosis. This study sought to clarify how patients with a malignant polyp were being colonoscopically surveilled if they did not undergo colorectal resection. METHODS: A retrospective, population-wide cohort analysis of all patients from 2011 to 2019 was performed using data from the Queensland Oncology Repository. Patient, procedural and pathological data were extracted for all patients diagnosed with a malignant polyp and timing of the first surveillance endoscopy was calculated. Statistical analysis comparing the timing of surveillance colonoscopy across multiple patients, procedural and histological characteristics were assessed. RESULTS: A total of 1646 patients were identified with a malignant polyp, with 797 patients managed with polypectomy and surveillance alone. The median time to surveillance endoscopy was 182 days with the mean 220.01 days. This was substantially sooner than the recommended clinical guidelines of 365 days. There were no patient or procedural characteristics which predicted a difference in the timing of surveillance colonoscopy. No pathological factors appeared to change the timing for surveillance endoscopy (P > 0.05). CONCLUSION: Overall, patients had surveillance endoscopy procedures substantially earlier than guideline recommendations. However, evidence underlying these guidelines and other surveillance methods for malignant polyps are not strong. Future technological developments, including improvements in imaging techniques, may provide additional options for surveillance of malignant polyps.

Deep Water Polymastiidae (Porifera, Polymastiida) from the South West Pacific.

This study reports on some deep water sponges in the family Polymastiidae collected during the 2017 Abyss Cruise off the East Coast of Australia and the 2003 NORFANZ Expedition to the Lord Howe and Norfolk Ridges in the Tasman Sea, Southwest Pacific Ocean. Species of Radiella, Spinularia, Ridleia, Tentorium and Polymastia were collected from abyssal and bathyal depths. From these collections, seven new species were discovered: Radiella nidula sp. nov., Radiella pumix sp. nov., Radiella sclera sp. nov., Spinularia flagellata sp. nov., Tentorium labium sp. nov., Ridleia echidna sp. nov. and Polymastia norfanzii sp. nov. In addition, two species previously known are redescribed based on the new collections: viz. Polymastia zitteli and Polymastia invaginata.

Revision of the genus Fascaplysinopsis, the type species Fascaplysinopsis reticulata (Hentschel, 1912) (Porifera, Dictyoceratida, Thorectidae) and descriptions of two new genera and seven new species.

The present study examines the taxonomy of sponge specimens with unique chemistry collectively known as Fascaplysinopsis reticulata (Hentschel, 1912). Examination of Hentschels original species upon which the genus Fascaplysinopsis Bergquist, 1980 was based in conjunction with a comparison with recent Indo-west Pacific collections, using morphological and molecular analyses (ITS and 28S rDNA), revealed extensive variation. Fascaplysinopsis reticulata was found to be a species complex comprising the genus Fascaplysinopsis, as well as two new genera: Skolosachlys gen. nov. and Rubrafasciculus gen. nov. The new species of Fascaplysinopsis described are F. palauensis sp. nov., F. klobos sp. nov. and F. ronquinni sp. nov. The new species of Skolosachlys gen. nov. described herein are: S. enlutea sp. nov. and S. nidus sp. nov. The new species described of Rubrafasciculus gen. nov. includes: R. cerasus sp. nov. and R. fijiensis sp. nov..

CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors.

BACKGROUND: High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs. EXPERIMENTAL DESIGN: We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo. RESULTS: We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts. CONCLUSION: Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy.

Rationale: An antibody-drug conjugate (ADC) is a targeted therapy consisting of a cytotoxic payload that is linked to an antibody which targets a protein enriched on malignant cells. Multiple ADCs are currently used clinically as anti-cancer agents significantly improving patient survival. Herein, we evaluated the rationale of targeting the cell surface oncoreceptor CUB domain-containing protein 1 (CDCP1) using ADCs and assessed the efficacy of CDCP1-directed ADCs against a range of malignant tumors. Methods: CDCP1 mRNA expression was evaluated using large transcriptomic datasets of normal/tumor samples for 23 types of cancer and 15 other normal organs, and CDCP1 protein expression was examined in 34 normal tissues, >300 samples from six types of cancer, and in 49 cancer cell lines. A recombinant human/mouse chimeric anti-CDCP1 antibody (ch10D7) was labelled with 89Zirconium or monomethyl auristatin E (MMAE) and tested in multiple pre-clinical cancer models including 36 cancer cell lines and three mouse xenograft models. Results: Analysis of CDCP1 expression indicates elevated CDCP1 expression in the majority of the cancers and restricted expression in normal human tissues. Antibody ch10D7 demonstrates a high affinity and specificity for CDCP1 inducing cell signalling via Src accompanied by rapid internalization of ch10D7/CDCP1 complexes in cancer cells. 89Zirconium-labelled ch10D7 accumulates in CDCP1 expressing cells enabling detection of pancreatic cancer xenografts in mice by PET imaging. Cytotoxicity of MMAE-labelled ch10D7 against kidney, colorectal, lung, ovarian, pancreatic and prostate cancer cells in vitro, correlates with the level of CDCP1 on the plasma membrane. ch10D7-MMAE displays robust anti-tumor effects against mouse xenograft models of pancreatic, colorectal and ovarian cancer. Conclusion: CDCP1 directed imaging agents will be useful for selecting cancer patients for personalized treatment with cytotoxin-loaded CDCP1 targeting agents including antibody-drug conjugates.