Translational Research Program Research Articles

7906 Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough In Targeting CYP17A1 For Castration Resistant Prostate Cancer Therapy

Abstract Disclosure: J. Yakubu: None. Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough in Targeting CYP17A1 for Castration Resistant Prostate Cancer Therapy. Jibira Yakubu a,b,c, Oya Taritd, Evangelos Natsaridisd, Amit V. Pandey a,ba Translational Hormone Research Program, Department of Biomedical Research, Faculty of Medicine, b Paediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital, Inselspital, Bern, c Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. d Biointerfaces, Institute of Chemistry and Bioanalytics, University of Life Sciences FHNW, Muttenz, Switzerland. Abstract: Androgens play a pivotal role in prostate cell survival and are implicated in both early-stage and advanced, castration-resistant prostate cancer (CRPC). In CRPC patients on CYP17A1 inhibitors, the development of drug resistance and hypertensive crisis through the inhibition of CYP21A2 and or its substrate are a recognized challenge. Given its crucial role in androgen production, CYP17A1 has become a major target for cancer therapies. In this study, we employed a mini-evaporation technique to nanoencapsulate curcumin, exploring its impact on CYP17A1 activity in human adrenal NCI-H295R cells. We performed steroid profiling with LC-MS, as well as gene and protein expression studies. Initial results demonstrated that curcumin nanoparticles exhibited superior efficacy in reducing CYP17A1 activity compared to known drug Abiraterone acetate. Curcumin and piperine combined in nano-capsules greatly increased the inhibitory effects on CYP17A1 activity. Furthermore, ongoing studies include western blot investigation of the drug's interaction with the CYP17A1 protein and cell cycle effects. We confirmed the efficacy of our nano formulation by testing its impact on the growth of androgen-sensitive prostate cancer cell lines. Notably, nanoencapsulation improved curcumin's inhibitory effects on DHEA production via CYP17A1. Surprisingly, the curcumin-piperine nano-capsules enhanced these effects while having no effect on CYP21A2, offering a promising option for prostate cancer treatment. Our study reveals the promise of nanoencapsulated curcumin-piperine as a game-changing method for targeting CYP17A1 for improved prostate cancer therapy. The synergistic benefits observed in our study open new avenues for addressing the difficulties associated with androgen deprivation therapy. Funding: Cancer Research Switzerland grant number: KFS 5557-02-2022 Presentation: 6/3/2024

Cognitive Dysfunction in the Addictions (CDiA): A Neuron to Neighbourhood Collaborative Research Program on Executive Dysfunction and Functional Outcomes in Outpatients Seeking Treatment for Addiction.

Substance use disorders (SUDs) are pressing global public health problems. Executive functions (EFs) are prominently featured in mechanistic models of addiction. However, there remain significant gaps in our understanding of EFs in SUDs, including the dimensional relationships of EFs to underlying neural circuits, molecular biomarkers, disorder heterogeneity, and functional ability. To improve health outcomes for people with SUDs, interdisciplinary clinical, preclinical and health services research is needed to inform policies and interventions aligned with biopsychosocial models of addiction. Here, we introduce Cognitive Dysfunction in the Addictions (CDiA), an integrative team-science and translational research program, which aims to fill these knowledge gaps and facilitate research discoveries to enhance treatments for people living with SUDs. The CDiA Program comprises seven complementary interdisciplinary projects that aim to progress understanding of EF in SUDs and investigate new biological treatment approaches. The projects draw on a diverse sample of adults aged 18-60 (target N=400) seeking treatment for addiction, who are followed prospectively over one year to identify EF domains crucial to recovery. Projects 1-3 investigate SUD symptoms, brain circuits, and blood biomarkers and their associations with both EF domains (inhibition, working memory, and set-shifting) and functional outcomes (disability, quality of life). Projects 4 and 5 evaluate interventions for addiction and their impacts on EF: a clinical trial of repetitive transcranial magnetic stimulation and a preclinical study of potential new pharmacological treatments in rodents. Project 6 links EF to healthcare utilization and is supplemented with a qualitative investigation of EF-related barriers to treatment engagement for those with substance use concerns. Project 7 uses innovative whole-person modeling to integrate the multi-modal data generated across projects, applying clustering and deep learning methods to identify patient subtypes and drive future cross-disciplinary initiatives. The CDiA program has promise to bring scientific domains together to uncover the diverse ways in which EFs are linked to SUD severity and functional recovery. These findings, supported by emerging clinical, preclinical, health service, and whole-person modeling investigations, will facilitate future discoveries about cognitive dysfunction in addiction and could enhance the future clinical care of individuals seeking treatment for SUDs.

Is it the people or the place? The remarkable 30-year period of integrative physiology research in the Carlson Gymnasium at the University of Colorado Boulder.

Historically, programs of physical education and sport were housed in gymnasium buildings on academic campuses. As physical education evolved to the more scientifically focused successor departments of exercise science and kinesiology, faculty specialization developed in the physiology of exercise. With time, some faculty broadened their research to study the integrative physiology of other biological states and stressors. Through this series of events, a small group of integrative physiologists was formed in the Carlson Gymnasium at the University of Colorado Boulder during the 1990s with the goal of conducting novel biomedical research. The challenges were daunting: no contemporary core laboratory facilities, lack of temperature control, piercing external noise, pests, regular flooding, electrical power outages, and lack of funds for renovation. Despite these obstacles, the group established an innovative program of translational physiological research ranging from high-throughput molecular analyses to cell models to rodent studies to clinical trials in humans. These investigators supported their work with grant awards from the National Institutes of Health (NIH), Department of Defense, National Aeronautics and Space Administration (NASA), American Heart Association, and private research foundations totaling ∼$80 M in direct costs from the late 1980s to 2020. Collectively, the faculty and their laboratory personnel published ∼950 articles in peer-reviewed scientific journals. Over that period, 379 undergraduate students, 340 graduate students, 84 postdoctoral fellows, and dozens of junior research faculty received scientific training in Carlson, supported by >$21 M in extramural funding. What was accomplished by this handful of integrative physiologists speaks to the importance of the qualities of the investigators rather than their research facilities in determining scientific success.

Multiomic factor analysis for pathologic complete response (pCR) after 12 weeks of pembrolizumab + trastuzumab + pertuzumab in HER2-enriched (HER2-E) early breast cancer (eBC) in the Keyriched-1 trial.

590 Background: pCR successfully identified candidates for (chemotherapy) de-escalation in the ADAPT HER2+ trial program. Here, we report biomarker analysis for pCR in the single arm, hypothesis-generating Keyriched-1 trial (NCT03988036) in HER2-E eBC treated with pembrolizumab and dual HER2 blockade. The trial rationale is based on high efficacy of anti-HER2 agents and potentially high immunogenicity and immune checkpoint protein expression in HER2-E eBC. Methods: 48 patients with HER2 2+ (ISH+) or 3+ eBC (stage I-III) and HER2-E subtype received pembrolizumab (200 mg), trastuzumab biosimilar (loading dose, LD 8 mg/kg, maintenance dose, MD 6 mg/kg), and pertuzumab (LD 840 mg/kg, MD 420 mg/kg) q3w for 12 weeks. Primary outcome was pCR (ypT0/is ypN0). Multiomic factor analysis was performed using different combinations of biomarker datasets: baseline BC360 single genes and gene signatures, multiplexed immunohistochemistry (mIHC), stromal tumor infiltrating lymphocytes (sTILs), somatic mutations and tumor mutational burden, and changes in circulating tumor DNA status under therapy. Factors representing combined markers developed from these pooled datasets were identified based on eigenvalue >1 criteria. Logistic regression with factors dichotomized by median score was conducted to analyze their association with pCR. Furthermore, logistic regression with elastic net regularization was performed using all single markers, factors from multiomic factor analysis, and clinical characteristics. Results: Factor involving gene expression (mainly related to immune response and tumorigenesis), mIHC markers (immune and HER2) in stroma, and sTILs datasets was significantly associated with pCR. Using the median as cutoff, higher scores increased the odds of pCR (unadj. OR 5.00, 95%CI 1.35, 18.56; p=.016). pCR rates were 66.7% and 28.6% in the high and low score groups, respectively. Effect of the factor (high vs low; OR 2.19) was also important in a model that additionally included clinical markers: grade (3 vs 2; OR 2.57), ER status (ER+ vs ER-; OR 0.89), cT (cT 2/3 vs 1; OR 0.69), cN (cN 1/2 vs 0; OR 0.51), and PR status (PR+ vs PR-; OR 0.34). When standardized values for all individual markers from gene expression, mIHC, and sTIL datasets were analyzed, markers with greatest impact on pCR vs. non-pCR were genes FNBP1, CD36, MYCN, and SIX1 (OR 1.43-1.62) and PR status (OR 0.65), with stronger impact than grade (OR 1.22) or nodal status (OR 0.90). Conclusions: Our multiomic analysis uncovered potential biomarkers for pCR in HER2-E eBC treated with immune therapy and dual-HER2 blockade alone. These results together with the results from the ADAPT translational research program support validation in larger trials investigating chemotherapy-free regimens in selected patients with HER2+ eBC. Clinical trial information: NCT03988036 .

Effects of neutralization of tumor-derived immunosuppressant GDF-15 on anti-PD-1 activity in anti-PD-(L)1 relapsed/refractory non-squamous NSCLC, urothelial, and hepatocellular cancer.

2513 Background: Growth and Differentiation Factor 15 (GDF-15) plays a critical role as potent, local immunosuppressant during pregnancy. Here we report for the first time data identifying GDF-15 as immunosuppressant in non-sq NSCLC, urothelial (UC) and hepatocellular (HCC) cancer and provide clinical evidence that GDF-15 blockade with visugromab can restore anti-PD1 activity in last-line, anti-PD1-(L)1 r/r patients with these tumors. Methods: A large translational research program, analyzing > 11.000 tumors in The Cancer Genome Atlas (TCGA) and paired serum/tumor samples for GDF-15 impact on the tumor microenvironment was conducted. In the GDFather ph2a first-in-human visugromab trial, subjects with advanced-stage, anti-PD1/PD-L1 relapsed/refractory (r/r) last-line solid tumors received the GDF-15 neutralizing antibody visugromab (CTL-002) at 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W om three defined expansion cohorts (NSCLC:n=5 2, UC :n=34, HCC: n=16). All patients were either (1) primary refractory to or (2) relapsed on continued checkpoint inhibitor (CPI) therapy after initial response, with all patients having received minimum of 12 weeks of continuous prior anti-PD-1/-L1 exposure. Primary endpoint was ORR. Results: In in-silico TCGA analyses, an inverse correlation between GDF-15 mRNA expression and key immune-related signatures revealed potent immunosuppression of several solid tumors including non-sq NSCLC and UC by GDF-15. In addition, in newly diagnosed, early-line UC patient samples, correlation of GDF-15 serum levels with reduced density of CD8+ T cells and immune cell proliferation (CD45+ki67+) was demonstrated. In the ph2a trial, visugromab + nivolumab showed excellent overall tolerability in heavily pre-treated patients, with just 6.9% of patients experiencing CTCAE Grade ≥ 3 treatment-related adverse events across these three indications. The observed ORR as per RECIST v1.1 criteria was 13.5% (5/37, 4PR, 1CR) in non-sq NSCLC, and 0% (0/15) in sq-NSCLC, in line with the translational research data. In UC, ORR was 17.6% (6/34, 5 PR, 1CR), and in HCC 18.8% (3/16, 2PR, 1CR); with 25 pts continuing on treatment, respectively. Duration of response (DoR) is surpassing 12 months for non-sq and UC lead cohort patients (N = 27 each) already, and 10/14 responses are ongoing. Conclusions: These analyses presented identify GDF-15 as novel, potent immunosuppressant in the tumor microenvironment of non-sq NSCLC, UC and HCC and identify it as potential key cause for CPI resistance. In heavily pretreated, by strict criteria anti-PD-1/-L1 r/r, late/last-line patients with NSCLC, UC and HCC, neutralization of GDF-15 by visugromab in combination with nivolumab resulted in an ORR of 16.1% (14/87; 11 PR and 3 CR) across these indications and long durability. Clinical trial information: NCT04725474 .

126 20 YEARS SHAPING A NEW GENERATION OF HISPANIC CLINICAL AND TRANSLATIONAL RESEARCHERS: UPR-MSC POSTDOCTORAL MASTER IN CLINICAL & TRANSLATIONAL RESEARCH PROGRAM

OBJECTIVES/GOALS: This project presents the Post-doctoral Master of Science in Clinical and Translational Research (MSc) program’s outcomes in 20 years of its implementation. This program is a joint offering between the Schools of Health Professions and School of Medicine of the University of Puerto Rico. METHODS/STUDY POPULATION: This study consists of secondary data analysis of academic and administrative documents. It also includes data from the Annual Evaluation retreats reports and an Alumni Follow-up Survey using an electronic questionnaire. All 121 Scholars admitted to the program from academic years 2003 to 2023 were included in the sample. Data analysis included descriptive statistical analysis of quantitative data and qualitative content analysis regarding recruitment/admissions, faculty composition, curriculum design, Scholars’ outcomes, and program’s financial support sources. Quantitative data were analyzed using the statistical software SPSS. RESULTS/ANTICIPATED RESULTS: Scholars of the program had been recruited from the UPR-MSC and several partner institutions with diverse backgrounds, disciplines, and research areas. Faculty and committee members have representation from the six MSC-Schools and partner institutions. The academic Program structure has changed over the years, and currently, more than 65% of the courses are offered online. Several financial sources have been identified to support the scholars. The Scholars’ portfolios of grant submission and publication productivity evidence the program’s success. Graduates have also been successful in advancing to positions that foster research impacting Hispanics. DISCUSSION/SIGNIFICANCE: The Post-doctoral Master’s in Clinical and Translational Research program (MSc) has contributed to the formation of committed Hispanic clinical and translational researchers impacting minorities and contributing to diversity in the research workforce.

122 Evaluating the impact of the Translational Research Program at the University of Toronto

OBJECTIVES/GOALS: There is a need to develop a workforce of translational research professionals with the skills to innovate, mobilize, and commercialize research for unmet needs in the Canadian health system. The objective of this study is to evaluate the impact and value of the master’s degree on the Translational Research Program (TRP) alumni. METHODS/STUDY POPULATION: This study will use a cross-sectional approach and an electronic survey will be administered to alumni. The TRP was established in 2015 and has graduated over 150 students since its inception. Participants will be recruited through convenience sampling via email, social media platforms, and personal communication. Eligible participants must have a conferred Master of Health Science in Translational Research from the University of Toronto. All collected data will remain anonymous and include demographic information about graduation year, race, ethnicity, gender, and employment status. Descriptive statistics will be used to analyze and report the findings. RESULTS/ANTICIPATED RESULTS: The results of this survey will be used to evaluate how the TRP graduate degree helps alumni contribute to healthcare, learn to think differently, and establish their professional networks. The findings will also be used to inform curriculum improvements, enhance competency-based assessments, and understand demographic differences in student cohorts to promote equity, diversity, and inclusion. Investigating the perspectives of alumni reflecting on their degree will support validating the program’s objectives and advance the integration of translational science principles in the healthcare workforce and community. DISCUSSION/SIGNIFICANCE: This research addresses the need to evaluate health sciences education to ensure the program’s novel pedagogical approaches are equipping the next generation of health professionals with the skills to accelerate the transformation of discoveries into interventions that benefit human health, improve clinical medicine, and enhance patient care.

Abstract 1852: NCI’s Clinical Proteomic Tumor Analysis Consortium: A proteogenomic cancer analysis program

Abstract The National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (NCI’s CPTAC) is a national effort to accelerate the understanding of cancer biology through the integration of large-scale proteome and genome analysis, or proteogenomics. The program which is composed of a Tumor Characterization Program and a Translational Research Program (proteomics.cancer.gov) aims to leverage the investments made in cancer research by understanding the molecular changes by proteogenomically characterizing cancers and accelerating the basic discovery toward clinical impact. All data and analytical tools are made broadly available to the research community through public databases to maximize utility and public benefit.CPTAC teams have characterized a plethora of treatment-naïve tumor types, including colorectal, ovarian, breast, clear cell renal cell carcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, brain (including adult, pediatric, and adolescent and young adult), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma (proteomics.cancer.gov/resources/milestones-and-publications). Ongoing projects include acute myeloid leukemia (AML), cutaneous melanoma, sarcoma, oligodendroglioma, gastric, prostate, liver, and thyroid cancers. In the PTRC Program, CPTAC is partnering with NCI-sponsored clinical trials to support clinically relevant research projects that would elucidate biological mechanisms of therapeutic response, resistance, and/or toxicity in cancers including AML, multiple myeloma, melanoma, and lung cancers. All mass spectrometry-based proteomic, genomic, and imaging data (histopathology and radiology) are made publicly available at the CPTAC Proteomic Data Commons (pdc.cancer.gov), Genomic Data Commons (gdc.cancer.gov), and the Cancer Imaging Archive (cancerimagingarchive.net)/Imaging Data Commons (imaging.datacommons.cancer.gov) respectively. CPTAC is also supporting development of new proteogenomic data analysis tools (proteomics.cancer.gov/resources/computational-tools). In addition, the CPTAC Assay Portal (assays.cancer.gov) is a public resource populated with mass spectrometry-based targeted proteomic assays developed by the consortium for quantitatively measuring proteins of interest, including those discovered through comprehensive tumor characterization. Lastly, well-characterized monoclonal antibodies targeting cancer-specific proteins and peptides are also made available at CPTAC’s Antibody Portal (antibodies.cancer.gov). Citation Format: Mehdi Mesri, Eunkyung An, Xu Zhang, Jasmin Bavarva, Ana I. Robles, Tara Hiltke, Henry Rodriguez. NCI’s Clinical Proteomic Tumor Analysis Consortium: A proteogenomic cancer analysis program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1852.

BIOSKIN: A Protocol for the Copenhagen Translational Skin Immunology Biobank and Research Programme

IntroductionPsoriasis, atopic dermatitis and contact dermatitis are common chronic inflammatory skin diseases that have a significant impact on individuals and society.Methods and analysisThe Copenhagen Translational Skin Immunology Biobank and Research...

Multicenter randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma receiving checkpoint inhibitors: the NORDIC-SUN-Trial

BackgroundPrimary tumor removal by cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma patients has been investigated in the context of various treatment regimens. Two randomized controlled trials investigated the role and timing of cytoreductive nephrectomy in the era of targeted therapy and demonstrated that upfront nephrectomy should no longer be performed when patients require systemic therapy. Superiority of checkpoint immunotherapy agents has led to a paradigm change from targeted therapies to immunotherapy-based first-line treatment in patients with primary metastatic disease; thus, deferred cytoreductive nephrectomy needs to be verified in the immunotherapy setting. Furthermore, a need exists for personalizing treatment choices for the individual patient to avoid unnecessary overtreatment.Methods/designTo explore the impact of cytoreductive nephrectomy in this patient group receiving checkpoint immunotherapy, we initiated a randomized, controlled trial comparing deferred cytoreductive nephrectomy with no surgery. The trial integrates a comprehensive translational research program with specimen sampling for biomarker analysis.DiscussionThe trial aims to show that deferred cytoreductive nephrectomy improves overall survival in patients with synchronous metastatic renal cell carcinoma, and furthermore, to identify relevant biomarkers for personalized renal cancer management.Trial registrationClinicalTrials.gov NCT03977571 June 6, 2019.

Machine Learning-assisted immunophenotyping of peripheral blood identifies innate immune cells as best predictor of response to induction chemo-immunotherapy in head and neck squamous cell carcinoma – knowledge obtained from the CheckRad-CD8 trial

PurposeIndividual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC. MethodsThe peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy. ResultsThe tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent. ConclusionsOur analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC.

Expanding pathways to clinical and translational research training with stackable microcredentials: A pilot study.

The proportion of physician-investigators involved in biomedical research is shrinking even as the need for high-quality, interdisciplinary research is growing. Building the physician-investigator workforce is thus a pressing concern. Flexible, "light-weight" training modalities can help busy physician-investigators prepare for key stages of the research life cycle and personalize their learning to their own needs. Such training can also support researchers from diverse backgrounds and lighten the work of mentors. The University of Pittsburgh's Institute for Clinical Research Education designed the Stackables Microcredentials in Clinical and Translational Research (Stackables) program to provide flexible, online training to supplement and enhance formal training programs. This training utilizes a self-paced, just-in-time format along with an interactive, storytelling approach to sustain learner engagement. Learners earn badges for completing modules and certificates for completing "stacks" in key competency areas. In this paper, we describe the genesis and development of the Stackables program and report the results of a pilot study in which we evaluated changes in confidence in key skill areas from pretest to posttest, as well as engagement and perceived effectiveness. Our Stackables pilot study showed statistically significant gains in learner confidence in all skill areas from pretest to posttest. Pilot participants reported that the module generated high levels of engagement and enhanced their skills, knowledge, and interest in the subject. Stackables provide an important complement to formal coursework by focusing on discrete skill areas and allowing learners to access the training they need when they need it.

Building our research administrator workforce as our clinical and translational research programs become increasingly complex.

Introduction: Research administrators (RA's) are critical members of the research workforce. For purposes of this article, research administrators are personnel who support the development, compliance, management, and financial oversight of sponsored research. There are currently very few institutional career development and mentoring programs available to research administrators. Recruitment and retention of quality research administrators has been especially challenging across the country in recent years. Methods: In an effort to address this gap in training and to increase recruitment and retention, the integrated Translational Health Research Institute of Virginia (iTHRIV), a collaborative NIH-NCATS funded Clinical Translational Science Award (CTSA) hub, has developed an innovative program of workforce development and mentoring for research administrators. This article provides an overview of one institutional training and development initiative, the Research Administration Program for Training and Resources (RAPTR). RAPTR provides training, resources and mentoring to develop a Community of Practice. Results: The program provides a forum where research administrators can share ideas, practices, and challenges. Discussion: This manuscript describes the benefits and lessons learned from our early experience in this program. We highlight selected components that may be generalizable to other institutions and describe individualized components, which require local policies and processes.

Evaluating Collaboration in a Translational Research Ecosystem

A core challenge of a multidisciplinary and multi-organizational translational research program is to set up and promote collaboration between researchers, labs, and organizations. Although the literature has studied and provided guidelines for collaboration, little has been written on how to evaluate it in large research projects and in a practical way. This study aims to identify dimensions and barriers to evaluating and leveraging collaboration in a large translational research ecosystem related to developing phytotherapy-based cancer treatments. By applying the Collaboration Evaluation and Improvement Framework (CEIF), our paper adds value by developing a methodological design for evaluation, incorporating mixed data in a real research ecosystem. Empirical findings provide support for applying the assessment approach and show that a research project’s sustainability depends on several collaboration factors and barriers at the socio-technical, management, operational, and institutional levels. Research results provide valuable insights for managing and improving collaborative efforts in large research groups, by anticipating collaboration issues with actionable and opportune strategies that can enhance the planning process, ecosystem performance, sustainability, research outcomes, and the program’s overall success. As a result, monitoring governance, management, leadership, and social relationships throughout the different phases of a translational research program is crucial in assessing and promoting collaboration.

Autres cibles addictives (KRAS, RET, HER2, NTRK…): Other addictive targets (KRAS, RET, HER2, NTRK…)

The prognosis of advanced Non-Small Cell Lung Cancer (NSCLC) has been significantly improving ever since the discovery of oncogenic driver alterations and the implementation of targeted therapies. Today, molecular profiling, preferably by using next-generation sequencing panels as well as liquid biopsies is crucial before starting treatment in patients with non-squamous NSCLC independent of their smoking status, as well as in those with squamous NSCLC who are little or non-smokers. In this review, we present the latest evidence on the most detected driver alterations in advanced NSCLC apart from EGFR, BRAF, ALK and ROS1. A few of the novel therapies have been approved in Europe in specific settings, and many are still not reimbursed by third-party payers. This highlights the importance of encouraging patients to participate in clinical trials to gain access to innovative treatments. Translational research programs are also important to uncover mechanisms of resistance to targeted therapies and how to overcome them.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

The International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting

The International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting

The FOxTROT platform: Clinical trials and exploratory research for personalization of neoadjuvant (NA) therapy in locally advanced colon cancer (LACC)—ISRCTN83842641.

TPS3636 Background: The FOxTROT1 trial demonstrated a significant reduction in 2-year (yr) recurrence with 6 weeks (wks) of oxaliplatin and fluoropyrimidine (OxFp) NA chemotherapy (NAC) in patients (pts) with LACC, establishing NAC as a new therapeutic option. The ongoing FOxTROT platform will refine and personalize NA therapy in LACC. FOxTROT2 is testing NAC in older pts and those with frailty, who are poorly represented in clinical trials. FOxTROT3 is assessing intensified NAC with modified FOLFOXIRI (mFOLFOXIRI; 5-fluorouracil, oxaliplatin, irinotecan) in fit pts. The FOxTROT platform will also test targeted treatments with established safety and efficacy in defined molecular subgroups. FOxTROT4 is investigating the efficacy and safety of NA encorafenib and cetuximab in BRAF-mutant pMMR LACC. Other arms in setup are shown in Table. Methods: FOxTROT platform trials are international, multicenter, open-label, phase II/III RCTs. Pts with resectable, cT3-4 N0-2 M0, biopsy-proven colon adenocarcinoma are eligible for recruitment. Pts whose age or frailty precludes mFOLFOXIRI can be considered for FOxTROT2. Pts suitable for mFOLFOXIRI can be considered for FOxTROT3. BRAF-mutant pMMR pts can be considered for FOxTROT4. Pts are randomized 2:1 between intervention and control arms. FOxTROT2 randomizes between 6 wks OxFp NAC (choice of 100% or 80% dose) vs proceeding straight to surgery. Adjuvant chemotherapy (AC) is per physician choice. Primary outcome is 3-yr DFS. 759 pts will be recruited over 5 yrs. FOxTROT3: 6 wks mFOLFOXIRI NAC vs 6 wks OxFp NAC. All pts receive AC but physicians may de-escalate mFOLFOXIRI to OxFp. Hierarchical co-primary endpoints: tumor regression grade (TRG) (blinded central assessment) and 3-yr DFS. 873 pts over 5 yrs. FOxTROT4: 6 wks NA encorafenib and cetuximab vs 6 wks OxFp NAC. AC is per physician choice. Primary outcome: TRG. 45 pts over 3 yrs. Secondary outcomes include: histopathological endpoints, downstaging, minimal residual disease by ctDNA, safety, toxicity, OS, surgical outcomes and patient-reported outcomes; and DFS in FOxTROT4. The FOxTROT platform opened 7th Feb 2022, funded by Yorkshire Cancer Research. At submission, 50 pts had been randomized at 23 centers. Trial design and management is conducted in partnership with patient representatives. A program of translational and radiomics research is running in parallel. International recruitment in France and India will commence in 2023 with additional international partners joining from 2024. Clinical trial information: ISRCTN83842641 . [Table: see text]

Editorial introductions.

Current Opinion in Organ Transplantation was launched in 1996. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of organ transplantation is divided into 18 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Editors-in-Chief, Associate Editor and Section Editors for this issue. SECTION EDITORS Matthew HartwigMatthew HartwigDr. Hartwig is a thoracic surgeon with a clinical focus in robotic assisted minimally invasive thoracic surgery for the treatment of diseases of the chest. He serves as the Surgical Director of the Esophageal Center at Duke. He is also the Director of the Minimally Invasive Thoracic Surgery Fellowship at Duke, while providing advanced instruction in robotic surgery to surgeons around the world. He also leads a successful program of clinical, basic and translational research in thoracic surgery and lung transplantation. He currently directs the Duke Ex Vivo Organ Laboratory (DEVOL), is the Chief of Lung Transplant Research, and is a faculty member at the Duke Clinical Research Institute (DCRI). John L.R. ForsytheJohn L.R. ForsytheProfessor John Forsythe was first appointed as a Consultant Transplant Surgeon at the Royal Infirmary of Edinburgh, UK in 1995. Prior to this, he was a Consultant Surgeon with special interest in renal transplantation at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. He is currently an Organ Utilisation Consultant for NHSBT, working with all departments of health for the UK. Professor Forsythe has held many professional committee appointments, among them Lead Clinician for Organ Donation and Transplantation in Scotland, Chairman of the Scottish Donation and Transplant Group and Chairman of the Safety of Blood, Tissues and Organs Advisory Committee to all four UK health ministers. He is a Past President of the British Transplantation Society and remains Honorary President of the British Society for Histocompatibility and Immunogenetics. Shunji NagaiShunji NagaiDr. Shunji Nagai is a general surgeon in Detroit, Michigan and is affiliated with Henry Ford Hospital. He received his medical degree from Nagoya University- School of Medicine and has been in practice for more than 20 years.

Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The GDFATHER-TRIAL).

2501 Background: Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical role in tumoral immunosuppression. Apart from blocking immune-cell entry into the tumor microenvironment, GDF-15 also has a major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block immunotherapy success. Here we report initial results of the phase 2a part of the GDF-15 neutralizing antibody visugromab (CTL-002) in combination with nivolumab. Methods: At cut-off date (06-Feb-2023), a total of 79 pts with advanced/metastatic solid tumors have been enrolled and were treated with visugromab 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W in the phase 2a expansion part of the CTL-002-001 phase 1/2 trial (NCT04725474). The primary endpoint of the phase 2a expansion is the Objective Response Rate (ORR) according to RECIST v1.1. Tumor assessments were performed every 8 weeks and patients had to be relapsed/refractory to a minimum of 12 weeks continuous prior anti-PD1/-PD-L1-containing therapy, with relapse or progression after initial response to have occurred on continued anti-PD1/PDL1 therapy. Phase 2a contained several indication-specific expansion cohorts (e.g. NSCLC, Bladder Cancer, HCC, Melanoma), following a Simon 2-stage design, and two cohorts were already expanded to stage 2 in light of initial responses observed. An additional expansion cohort is a pan-tumor basket cohort with sequential tumor biopsies for biomarker analyses. A key component of this multi-arm trial is an extensive translational research program to identify response-predictive tumor and immunologic marker and pattern. Results: Across several expansion cohorts, durable tumor regressions were observed, including several partial responses (PR) and one complete response (CR) in heavily pretreated patients with a median of 3 prior lines of systemic therapy for advanced/metastatic cancer, including at least one prior line of anti-PD1/-PD-L1 therapy and being relapsed/refractory to it. In NSCLC, so far 13 pts underwent at least one tumor assessment. Of these, two experienced a PR (one confirmed), three additional tumor shrinkage > 5% (TS) and one longer-term SD (LT-SD) were seen. In bladder cancer, 7 patients underwent at least one tumor assessment with 1 confirmed CR, 1 TS and 1 LT-SD. The treatment was overall well tolerated. Conclusions: These initial phase 2a results demonstrate promising clinical activity for the combination of visugromab and nivolumab in heavily pretreated anti-PD1/-PD-L1 refractory/relapsed solid tumor patients across various indications, including induction of confirmed partial and complete responses. Extensive biomarker evaluations are ongoing to further evaluate potential response-predictive markers identified during phase 1 development. Clinical trial information: NCT04725474 .

Study protocol of an open-label, single arm phase II trial investigating the efficacy and safety of Trifluridine/Tipiracil combined with irinotecan as a second line therapy in patients with cholangiocarcinoma (TRITICC)

BackgroundThe prognosis of patients with advanced biliary tract cancer (BTC) who have progressed on gemcitabine plus cisplatin is dismal. Trifluridine/tipiracil (FTD/TPI) and irinotecan have proven efficacy in different gastrointestinal malignancies. We therefore hypothesized that this combination might improve the therapeutic outcome in patients with BTC after failure of first line treatment.MethodsTRITICC is an interventional, prospective, open-label, non-randomised, exploratory, multicentre, single-arm phase IIA clinical trial done in 6 sites with expertise in managing biliary tract cancer across Germany. A total of 28 adult patients (aged ≥ 18 years) with histologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy will be included to receive a combination of FTD/TPI plus irinotecan according to previously published protocols. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment.DiscussionThe aim of TRITICC is to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with biliary tract cancer refractory to previous Gemcitabine based treatment.Trial registrationEudraCT 2018–002936-26; NCT04059562