bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive genomic analysis for homologous recombination deficiency in pancreatic cancer.
Authors: Jung Kwangrok , Jung Jae Hyup , Ahn Jinwoo , Kim Bomi , Lee Jong-Chan , Kim Jaihwan , Hwang Jin-Hyeok 
Published: June 2023

e15168 Background: Although homologous recombination deficiency (HRD) has been heavily studied in oncology, HRD in pancreatic cancer remains poorly understood beyond germline alterations in BRCA1, BRCA2 and PALB2. Methods: We performed whole exome sequencing (WES) on 205 patients with pancreatic cancer. Germline and somatic mutations in HRD genes were evaluated: (1) canonical HRD mutation ( BRCA1, BRCA2 and PALB2); and (2) non-canonical HRD mutation ( ATM, ATR, ATRX, CHEK2, BAP1, BARD1, BLM, BRIP1, NBN, RAD51 genes, RAD54 genes, FANC genes and ERCC genes). In addition, signature-based HRD classifiers were also applied: (1) the genomic instability score (GIS); (2) substitution base signature 3 (SBS3); and (3) small insertion and deletions 83B (ID83B). The frequency of HRD mutations and signatures-based HRD in pancreatic cancer were evaluated and their clinical utility were assessed by confirming the association with the response to platinum-containing chemotherapy. Results: Among the 205 patients, 41 patients (20.0%) were identified to harbor HRD mutations. Germline and somatic HRD mutations were identified in 19 (9.3%) and 24 (11.7%) patients, respectively. Mutations in canonical genes and non-canonical genes were found in 12 (5.9%) and 37 (18.1%) patients, respectively. Using signature-based HRD classifier, additional 45 (22.0%) patients were determined to be HRD. Among patients who received first-line FOLFIRINOX ( N = 113), canonical HRD mutation and signature-based HRD group showed higher response rate than non-canonical HRD and non-HRD group (75.0% and 57.1% vs. 31.3% and 33.3%, respectively). In the survival analysis of patients treated with FOLFIRINOX, canonical HRD and signature-based HRD group tended to have better overall survival than non-HRD group. Conclusions: Comprehensive genomic analysis could identify a significant number of HRD pancreatic cancer beyond germline BRCA1,2 and PALB2 mutation, and it would be helpful to choose the appropriate chemotherapy regimen.
Carcinoembryonic antigen (CEA) expression in human tumors: A tissue microarray study on 15,413 tumors.
Authors: Jansen Kristina , Kornfeld Lara , Lennartz Maximilian , Blessin Niclas C. , Höflmeyer Doris , Dwertmann Rico Sebastian , Kind Simon , Viehweger Florian , Fraune Christoph , Gorbokon Natalia , Hube-Magg Claudia , Menz Anne , Burandt Eike C. , Sauter Guido , Simon Ronald , Kluth Martina , Steurer Stefan , Marx Andreas H. , Minner Sarah , Bernreuther Christian 
Published: June 2023

e15181 Background: Carcinoembryonic antigen (CEA) is a cell surface glycoprotein which is overexpressed in various cancers but reported prevalence data vary considerably for many tumor types. Because of its overexpression in various cancer types and the limited expression in normal tissue CEA has become a potential drug target with several potential drug candidates currently being evaluated. CEA is also shed into the blood stream, so that CEA measurement in the serum is used as a tool for early detection and recurrence monitoring of cancer. Methods: To comprehensively determine CEA expression in normal and neoplastic tissues, a tissue microarray containing 15,413 samples from 120 different tumor types and subtypes as well as 76 different normal tissue types were analyzed by immunohistochemistry. Results: CEA was detectable in 65 (54.2%) of 120 tumor categories including 49 (40.8%) tumor types with at least one strongly positive case. CEA positivity was most common in colorectal adenomas (100%) and carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1%-80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), squamous cell carcinomas of various sites (30.2%-69.1%), and small cell carcinomas of the lung (64.3%), the urinary bladder (38.9%), and the prostate (50.0%) as well as non-invasive papillary urothelial carcinoma pTa G3 (33,6%), pTa G2 high-grade (25,0%) and pTa G2 low-grade (5,7%). High CEA expression was linked to high grade tumors (p < 0.0001) and invasive growth (p < 0.0001) in urinary bladder cancer as well as estrogen receptor positivity (p = 0.0005) and HER2 positivity (p = 0,0158) in invasive breast cancer of no special type. In 1.250 colorectal adenocarcinomas, reduced CEA expression was associated with mismatch repair deficiency (p < 0.0001) but not with pT and pN stage. CEA expression level was unrelated to clinico-pathological tumor parameters in adenocarcinomas of the pancreas and the stomach, endometroid endometrium carcinoma as well as in serous and endometroid carcinomas of the ovaries. Conclusions: In summary, CEA is abundantly expressed in a broad range of epithelial neoplasms. Our data thus identify various tumor entities where CEA positive cancers might best benefit from CEA serum monitoring and anti-CEA therapies.
Antiproliferative activity of marine-derived oligopeptides combined with androgen receptor inhibition in preclinical prostate cancer models.
Authors: Currie Crawford , Bjerknes Christian , Hermansen Erland , Framroze Bomi 
Published: June 2023

e15186 Background: Recent cancer statistics reveal a sustained increase in the incidence of prostate cancer (PC) of 3% per year. More than half of this increase is attributable to advanced disease. Advanced PC remains largely incurable, owing to inevitable progression. Escalation of therapy can restore tumor control, but significant sequelae may result. Anticancer peptides of marine origin appear intrinsically target specific and may constitute a novel approach to improve the therapeutic sensitivity of resistant cancers. Recently published in vitro work showed that a marine soluble protein hydrolysate (SPH) potentiated the anticancer effect of androgen-receptor inhibitors (ARis) in PC cells. SPH also induced transcriptional upregulation of ferritin heavy chain 1 (FTH1) in LNCaP and PC3 cell lines. Given the growing recognition that iron dysmetabolism plays a key role in PC, we applied the findings to this current study. Methods: Eight candidate FTH1-modulatory peptides (FT-001 to -008, all 7- or 8-mer peptides) were identified in the SPH peptide mix and subsequently sequenced and synthesized. Antiproliferative effects of individual FT peptides were assessed in combination with ARis (bicalutamide/BIC or enzalutamide/ENZ) in phenotypically distinct PC cell lines (LNCaP, PC3, VCaP, ENZR-VCaP) and compared to the inhibitory effect of SPH-ARi combination or ARi monotherapy. Results: FT-002 or -005 (10 μM concentration), showed significantly greater inhibition of LNCaP and PC3 cell viability when co-administered with BIC IC50 (0.4 μM & 10 μM respectively), than SPH (160 μM) with BIC or BIC monotherapy (p < 0.001). Similarly, either peptide combined with ENZ IC50 (1.4 μM) exhibited significant antiproliferative effects on androgen-sensitive VCaP cells when compared to SPH (160 μM) & ENZ co-treatment (p < 0.01) and ENZ monotreatment (p < 0.001). Both peptides (10 μM) produced a similar pattern of results in ENZ-resistant VCaP cells when treated with ENZ at its corresponding IC50 (47 μM) (p < 0.001). Differential gene expression profiling of all tested cells showed a consistent and significant upregulation of FTH1 and concomitant downregulation of transferrin receptor (TFRC) gene expression of greater than 2-fold for FT/ARi therapy. Conclusions: FT-002 and -005 synergistically combine with ARis to significantly attenuate PC tumor growth in vitro. Gene expression profiling implicates peptide-mediated FTH1 and TFRC modulation in the mode of action to interfere with tumor cell iron metabolism. Novel research perspectives implicate ferritin and FTH1 expression levels in prostate carcinogenesis and tumor progression. Further research in xenograft models is warranted, in order to validate the current findings and further investigate the cellular pathways responsible for the observed anticancer activity seen with FT-002 and FT-005.
Marketing approvals for cell and gene therapy products in oncology: Current review of EMA and FDA approvals.
Authors: Chandaria Rehma , Sripathirathan Kumar , Song Yun Jeong , Learn Chris A. 
Published: June 2023

e15189 Background: Cell and gene therapies (CGT) are emerging as potentially game-changing treatments for relapsing and refractory cancer. To date, there are 9 CGTs approved for different cancers across the US and EU, majority focused on autologous CAR-T cell therapies for hematological cancers. In addition, there are ~1500 CGTs in preclinical and clinical development for treatment of cancers utilizing diverse approaches. The risks involved with CGTs differ from small molecule and biologics, and therefore the data required to demonstrate their safety are also different. To get an insight into what regulatory agencies are looking for demonstrating safety for anticancer CGTs, we analyzed the supporting nonclinical studies for the currently approved therapies. Methods: We reviewed of the European Public Assessment Reports (EPAR) and FDA Summary Basis for Approval (SBA) documents for the 9 approved anticancer CGTs. In particular, we looked into approaches that were accepted by the regulatory agencies and the justification provided. Results: Of the 9 approved CGTs included in the review, there were 6 autologous CAR-T cell therapies for the treatment of different hematological malignancies, 1 PBMC-based cell therapy for prostate cancer, 1 gene therapy treatment for bladder cancer, and 1 oncolytic virus for melanoma. Of the different cell therapies, only for Carvykti was a non-human primate study conducted with autologous CAR-T cells. The absence of toxicity studies for the other cell therapies was justified by the lack of relevant animal models since autologous human cells do not work in immune competent animals. Safety data was gathered along with pharmacology studies and clinical studies. As stated in ICH guideline S9, genotoxicity and carcinogenicity studies are not essential to support clinical trials for therapeutics intended to treat patients with advanced cancer. However, there is a theoretical risk of insertional mutagenesis with gene therapies. This was addressed with the approved gene therapies using studies for integration site analysis and IL-2 independent growth, together with review of published literature and clinical data. Conclusions: The risks associated with each cell and gene therapy are unique. As the science continues to evolve, together with new technologies and approaches, existing regulatory guidance may not cover the nonclinical study requirements for all products. It is therefore crucial for drug developers to take a risk-based approach in determining the need for appropriate nonclinical safety studies. The application of 3Rs to reduce animal use is widely encouraged and therefore regulatory agencies accept lack of non-relevant animal models as well as other science-based justifications for not conducting conventional animal studies.
Influence of age, sex and tumor type in the likelihood of inclusion in early clinical trials.
Authors: Vieito Maria , Rojas Katerin Ingrid , Berché Roger , Viaplana Cristina , Lostes Julia , Galvao Vladimir , Alonso Guzman , Oberoi Honey Kumar , Brana Irene , Oliveira Mafalda , González Macarena , Felip Enriqueta , Saura Cristina , Carles Joan , Macarulla Teresa , Garralda Elena , Tabernero Josep , Saavedra Omar 
Published: June 2023

e15193 Background: Inclusivity in early drug development is essential for achieving consistent and accurate results. Sex-specific differences in biology and pharmacology should be explored as early as possible during clinical development. Lack of inclusion of elderly patients underestimates the risk of toxicity due to comorbidities and polypharmacy, but adolescents and young adult patients (AYAs) are even less represented in clinical trials, leading to slower improvements in survival. Methods: Patients referred for a first consultation to Vall de Hebron Institute of Oncology Early Drug Development Unit between 2019-2021 were analyzed. Clinical variables included: age, sex, primary tumor location, clinical trial inclusion and type of clinical trial. Results: On a total of 1218 pts, a total of 580 (48.53%) were included in at least 1 early clinical trial. The median age of the overall population was 61 y(ranging from 22 to 92), with no differences in pts included (62y) or not(60y) in clinical trials. Elderly patients ( > 75y) were 9.1% of the population referred and achieved a similar rate of inclusion (46.90% vs 49.44%) while AYAs(18 to 29-year-old) represented only 1.47% of pts referred and were only matched to a clinical trial in 33.33% of cases. (Fisher’s p-value = 0.06). Equal proportion of males and females were referred to clinical trials, with the exception of elderly patients (60.17% male) and AYAs(61.11%). the overall population). In the overall population the most common primary tumor locations were colorrectal (24.38%), other gastrointestinal tumors (18.14%) and breast cancer (10.91%). The most common primary tumor location in patients > 75y was colorectal(28.82%), other gastrointestinal tumors(19.81%) and head and neck(14.41%) vs sarcoma(38.88%), CNS(27.77%) and other gastrointestinal(11.1%) in AYA patients. Inclusion rates depending on the type of tumor ranged from 63% to 23%. Patients with genitourinary and gynecologic cancers had a statistically significant higher likelihood of being included in a clinical trial whereas sarcoma and primary CNS tumors had lower chances of being included in a clinical trial. In a binomial multivariant model the only factor predictive of inclusion in a early clinical trial was tumor type, whereas, sex, age group and availability of molecular profiling, was not statistically significant. Conclusions: Elderly patients with cancer and AYAs were referred less frequently to our unit that the overall prevalence of cancer in those populations and in the case of AYA pts the rate of inclusion lagged behind, driven mainly by the tumor types more common in each population.
Aluminium phthalocyanine–mediated photodynamic therapy promotes antitumour activity in oesophageal cancer stem cells.
Authors: Didamson Onyisi Christiana , Chandran Rahul , Abrahamse Heidi 
Published: June 2023

e15194 Background: Photodynamic therapy (PDT), a non-invasive treatment modality, has emerged as an effective treatment measure for various cancers, including oesophageal cancer. PDT has attracted much attention in the field of oncology due to its low toxicity profile and the selective accumulation of the photoactivated agent in the tumour cells. However, the therapeutic effect of Aluminium (III) Phthalocyanine Chloride Tetra sulfonic Acid (AlPcS4Cl) mediated PDT on oesophageal CSCs is limited. In this study, we evaluated the cellular localization of AlPcS4Cl and its PDT anticancer effects on oesophageal CSCs. Methods: An in vitro experimental design was employed in this study. Oesophageal cancer (HKESC-1 cells) was grown, and the CSCs were isolated using the magnetic-activated cell sorting (MACS). The isolated CSCs were characterised using a flow cytometry, Hoechst efflux side population test, and immunofluorescence. The CSCs were maintained in a serum-free culture medium and incubated at 37° C, 5% CO2 and 85% humidity. The cells were grouped into control and experimental groups. The CSCs received two-fold increasing concentrations of AlPcS4Cl and were exposed to irradiation at 673.2nm wavelength using a diode laser. After 24 hours post-PDT, the anticancer activities of AlPcS4Cl on oesophageal CSCs were examined. The MTT cell viability assay was used to determine the 50% inhibitory concentration (IC50), light microscopy for morphological changes, and adenosine triphosphate (ATP) assay for cell proliferation, lactate dehydrogenase (LDH) assay for cellular toxicity. While cellular localization of AlPcS4Cl was examined using fluorescent microscopy. All experimental and control cells were conducted in six biological replicates (n = 6). Results: Results were compiled, and statistical analysis was performed using GraphPad Prism (v5). The mean values of experimental groups were compared with the mean value of the control cells. One-way ANOVA was employed, and a p-value of less than 0.05 was considered statistically significant. Findings from cellular localization showed that the AlPcS4Cl is localized in the mitochondria and lysosomes, indicating a probable cellular death pathway. The dose-response of AlPcS4Cl on oesophageal CSCs showed an IC50 value of 4µM, suggesting the photosensitizer is efficient for the treatment of CSCs at low concentrations. The CSCs exposed to PDT showed remarkable morphological distortion, high cytotoxic activity, decreased viable cells and significant antiproliferative potential. Conclusions: This study showed that AlPcS4Cl promote PDT anticancer effects on oesophageal CSCs and could serve as an efficient therapeutic option for eradicating oesophageal CSCs.
Preliminary data from the phase I study of TCMCB07, a study to assess the safety, tolerability and pharmacokinetics of the melanocortin antagonist TCMCB07 in healthy subjects.
Authors: Qi LeAnn Kuhlmann , Zhu Xinxia , Gruber Kenneth , Roeland Eric J. , Potterfield Russell , Marks Daniel 
Published: June 2023

e15195 Background: Cachexia is a complex wasting syndrome characterized by anorexia, an involuntary loss of adipose tissue and lean body mass, and a paradoxical increase in energy catabolism. TCMCB07 is an optimized peptide antagonist of the melanocortin type 3 and 4 receptors for the treatment of cachexia. Several studies have been completed on TCMCB07 including: primary efficacy studies in rodent models of cachexia, studies to assess off-target activities, PK/ADME studies, and a 28-day GLP tox program in rats and dogs. Pre-clinical animal trials show significant results in ameliorating cancer and chronic kidney disease-associated cachexia. Based on these data, a phase 1 dose escalation study was conducted in healthy volunteers. Methods: The Phase 1 study of TCMCB07 (NCT05529849) is a single center, double-blind, randomized, sequential assessment of 5 single ascending dose cohorts (SAD) and 3 multiple ascending dose cohorts of TCMCB07. Subjects received subcutaneous administration of TCMCB07 or placebo on each of 5 consecutive days. Primary endpoints were safety and tolerability. The secondary endpoint was characterization of pharmacokinetics. Results: 40 subjects completed the SAD and 36 subjects completed the MAD portions of the trial. In a preliminary analysis of the results, there were no subjects with abnormal vital signs, no subjects with abnormal electrocardiograms, and no drug-related serious adverse events. The most common study-related adverse event was injection site reaction, graded 1 mild, or 2 moderate out of 5 (NCI CTCAE). Analysis of pharmacokinetics yielded Cmax and AUC higher than what was expected based on rat and dog studies. This resulted in lowering the cohort 3 dose so that the CMax would not exceed the cohort 5 SAD CMax. A weight difference in MAD cohort 2 and 3 between placebo and control was observed with the change in weight from end-of-study to baseline of 1.07 kg (p = 0.0195). In the same groups, on a VAS hunger scale, subjects taking TCMCB07 indicated 15% greater ease in eating meals compared to controls. This measure reached significance at one time point (p = 0.0497) but not at another (p = 0.0892). Conclusions: CB07 was well tolerated by normal healthy volunteers. Though the Phase 1 study was not designed to study efficacy, a modest difference was observed between placebo and active for body weight change and hunger. Results warrant further examination in a randomized Phase 2 study in cancer patients experiencing cachexia. Clinical trial information: NCT05529849 .
Effect of melanocortin-4 receptor antagonist TCMCB07 on chemotherapy-induced anorexia and weight loss in rats.
Authors: Zhu Xinxia , Roeland Eric J. , Norgard Mason A. , Gruber Kenneth , Potterfield Russell , Marks Daniel 
Published: June 2023

e15196 Background: We previously reported that peripheral administration of TCMCB07, a synthetic antagonist of the type 4 melanocortin receptor (MC4R), ameliorates cancer- and chronic kidney disease-associated cachexia in rats. In this study, we used a rat model of cisplatin and 5-FU to evaluate the efficacy of TCMCB07 in alleviating chemotherapy-induced anorexia, weight loss and muscle wasting. Methods: Two separate experiments were performed in a total of 58 rats. 1) Cisplatin (Cis)/TCMCB07 experiment with 3 groups: Cis/saline (n = 11), Cis/TCMCB07 (n = 11), Saline/saline (n = 6). 2) 5-FU/TCMCB07 experiment with 3 groups: 5-FU/saline (n = 12), 5-FU/TCMCB07 (n = 12), Saline/saline (n = 6). Rats were treated with Cis (2.5mg/kg), 5-FU (70 mg/kg), or saline via IP injection once weekly for 3 weeks. Rats were also treated with TCMCB07 (3 mg/kg/day) or saline via daily SC injection for 21 days. Food intake and body weight were measured daily. Body composition was analyzed pre- and post-treatment by MRI. Heart and gastrocnemius were dissected and weighed after euthanasia. Results: Total food intake over 21 days was significantly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0006) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0134), and decreased in Cis/saline vs Saline/saline group (p = 0.001), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/saline or 5-FU/TCMCB07 vs Saline/saline group. Body weight was robustly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0007) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0013), and decreased in Cis/saline vs Saline/saline group (p = 0.0001) and 5-FU/saline vs Saline/saline group (p = 0.0041), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/TCMCB07 vs Saline/saline group. Cardiac and skeletal muscle loss was markedly attenuated in Cis/TCMCB07 vs Cis/saline (cardiac: 3.12% vs -11.95%, p < 0.0001; skeletal: -3.88% vs -9.02%, p = 0.0259). Cardiac muscle loss was significantly attenuated in 5-FU/TCMCB07 vs 5-FU/saline group (1.40% vs -6.09%, p = 0.0131) and skeletal muscle was modestly changed (-4.17% vs -7.24%, p = 0.1782). While Cis/saline and 5-FU/saline groups lost 91.33% and 52.61% of fat mass respectively compared to Saline/saline group, Cis/TCMCB07 and 5-FU/TCMCB07 groups gained 37.68% (p = 0.0002) and 70.19% (p < 0.0001). Conclusions: This preclinical trial provides evidence supporting peripheral TCMCB07 antagonism of central melanocortin signaling, increasing food intake and anabolism, ultimately alleviating anorexia, weight loss and muscle wasting over multiple cycles of cisplatin or 5-FU chemotherapy.