Precision Medicine In Pancreatic Cancer Research Articles

Precision medicine for pancreatic cancer: Characterizing the clinico-genomic landscape and outcomes of KRAS G12C-mutated disease.

Mutated KRAS is the most common oncogene alteration in pancreatic cancer (PDAC), and KRAS G12C mutations (KRAS G12Cmut) are observed in 1-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including PDAC. Little is known regarding clinical, genomics and outcome data of this population. Patients with PDAC and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center (MSK), and via the AACR Project GENIE database. Clinical, treatment, genomic and outcomes data were analysed. A cohort of patients at MSK with non-G12C KRAS PDAC was included for comparison. Among 3,571 patients with PDAC, 39 with KRAS G12Cmut were identified (1.1%). Median age was 67 years, 56% were female. Median BMI was 29.2 kg/m2, 67% had a smoking history. Median OS 13 months (9.4, not reached (NR)) for stage IV, and 26 months (23, NR) for stage I-III. Complete genomic data (via AACR GENIE) was available for N = 74. Most common co-alterations included: TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (N = 2931) of non-G12C KRAS-mutated PDAC, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). OS did not differ between KRAS G12Cmut and non-G12C KRAS PDAC. Germline pathogenic variants were identified in 17%. N = 2 received KRAS G12C-directed therapy. PDAC and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated PDAC, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in PDAC provides a precedent for broader KRAS targeting in PDAC.

Investigating the anti-cancer compounds from Calliandra harrisii for precision medicine in pancreatic cancer via in-silico drug design and GC-MS analysis.

Pancreatic cancer is a fatal illness caused by mutations in multiple genes. Pancreatic cancer damages the organ that helps in digestion, resulting in symptoms including fatigue, bloating, and nausea. The use of medicinal plants has been crucial in the treatment of numerous disorders. The medicinal plant Calliandra Harrisi has been widely exploited for its possibilities in biology and medicine. The current study aimed to assess the biopotential of biologically active substances against pancreatic cancer. The GC-MS data of these phytochemicals from Calliandra Harrisi were further subjected tocomputational approaches with pancreatic cancer genes toevaluate their potential as therapeutic candidates. Molecular docking analysis revealed that N-[Carboxymethyl] maleamic acid is the leading molecule responsible for protein denaturation inhibition, having the highest binding affinity of 6.8 kJ/mol among all other compounds with KRAS inflammatory proteins. Furthermore, ADMET analysis and Lipinski's rule validation were also performed revealing its higher absorption in the gastrointestinal tract. The results of the hepatotoxicity test demonstrated that phytochemicals are non-toxic, safe to use, and do not cause necrosis, fibrosis, or vacuolar degeneration even at excessive levels. Calliandra Harrisi has phytoconstituents that have a variety of pharmacological uses in consideration.

Liquid biopsy in pancreatic cancer - Current perspective and future outlook.

Pancreatic cancer is a lethal condition with a rising incidence and often presents at an advanced stage, contributing to abysmal five-year survival rates. Unspecific symptoms and the current lack of biomarkers and screening tools hamper early diagnosis. New technologies for liquid biopsies and their respective evaluation in pancreatic cancer patients have emerged over recent years. The term liquid biopsy summarizes the sampling and analysis of circulating tumor cells (CTCs), small extracellular vesicles (sEVs), and tumor DNA (ctDNA) from body fluids. The major advantages of liquid biopsies rely on their minimal invasiveness and repeatability, allowing serial sampling for dynamic insights to aid diagnosis, particularly early detection, risk stratification, and precision medicine in pancreatic cancer. However, liquid biopsies have not yet developed into a new pillar for clinicians' routine armamentarium. Here, we summarize recent findings on the use of liquid biopsy in pancreatic cancer patients. We discuss current challenges and future perspectives of this potentially powerful alternative to conventional tissue biopsies.

Abstract LB163: A microfluidic platform for developing circulating tumor cells (CTCs) organoids for precision medicine in pancreatic cancer

Abstract Introduction Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer death in the US by 2030. Besides the late detection and lack of effective treatments, the greatest treatment hurdle to PDAC is the ineffectiveness of patient-derived tumor models. Precision medicine-based treatment decisions require the generation of consistent and trackable complex organoid models that is not achievable by tissue biopsies. Liquid biopsies such as blood, instead, contain circulating biomarkers released by the tumor, among which especially interested in for this study are circulating tumor cells (CTCs). This work develops microfluidic 3D organoids from CTCs to be used as a precision medicine tool to predict and guide the drug response of early stage I-IIB (PDAC) patients. Experimental Methods CTCs are isolated from PDAC patient blood samples using microfluidic Labyrinth following removal of red blood cells with 6% dextran. Collected cells post-isolation are immunofluorescence (IF) stained with DAPI (nuclei), CD45 (leukocyte), pancytokeratin (type I/II cytokeratin 1-8, 10, 14- 16 and 19), Vimentin, and Epithelial cell adhesion molecule (EpCAM) to identify CTCs and characterize their phenotypes. The mold of the microfluidic platform for CTC organoids is fabricated with the standard SU-8 photolithography. The PDMS-based device is tested with a low seeding number of a pancreatic cancer CTC cell line labeled fluorescently. Decellularization of cancer associated fibroblasts (CAFs) generates the in vitro matrix that supplies amino-acid precursors for PDAC metabolism, promoting CTC organoid formation. Serial images of cell growth are obtained throughout the course using a Ti-20 microscope. After each 7-day culture, organoids are dissociated from the device and IF stained using a similar panel as above (with Ki67 marker instead of CD45 for cell proliferation). Preliminary gemcitabine dosage-performance analysis is performed on-chip. Results CTC count from the tested patient panel (n=16) averages 17.0±8.4/mL of blood. CAFs are successfully decellularized on-chip and the embedded pancreatic CTC cell line growth curve is generated. IF staining of the dissociated cells from the organoids confirms the proliferation of the loaded pseudo-CTCs. Conclusion The work above demonstrates the successful isolation of CTCs from PDAC patient blood samples and an engineered microfluidic platform to expand low abundance of cells into organoids. It has a potential to be tested and employed to expand CTCs from PDAC into organoids for drug screening. Citation Format: Yu Zhang, Scott Smith, Minal Nenwani, Valerie Gunchick, Vaibhav Sahai, Sunitha Nagrath, Deepak Nagrath. A microfluidic platform for developing circulating tumor cells (CTCs) organoids for precision medicine in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB163.

Pancreatic Cancer Organoids: An Emerging Platform for Precision Medicine?

Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with remarkable resistance to treatment, poor prognosis, and poor clinical outcome. More efficient therapeutic approaches are urgently needed to improve patients' survival. Recently, the development of organoid culture systems has gained substantial attention as an emerging preclinical research model. PDAC organoids have been developed to study pancreatic cancer biology, progression, and treatment response, filling the translational gap between in vitro and in vivo models. Here, we review the rapidly evolving field of PDAC organoids and their potential as powerful preclinical tools that could pave the way towards precision medicine for pancreatic cancer.

Challenges in precision medicine in pancreatic cancer: A focus in cancer stem cells and microbiota.

Pancreatic cancer adenocarcinoma (PDAC) is a lethal disease, with the lowest 5-years survival rate of all cancers due to late diagnosis. Despite the advance and success of precision oncology in gastrointestinal cancers, the frequency of molecular-informed therapy decisions in PDAC is currently neglectable. The reasons for this dismal situation are mainly the absence of effective early diagnostic biomarkers and therapy resistance. PDAC cancer stem cells (PDAC-SC), which are regarded as essential for tumor initiation, relapse and drug resistance, are highly dependent on their niche i.e. microanatomical structures of the tumor microenvironment. There is an altered microbiome in PDAC patients embedded within the highly desmoplastic tumor microenvironment, which is known to determine therapeutic responses and affecting survival in PDAC patients. We consider that understanding the communication network that exists between the microbiome and the PDAC-SC niche by co-culture of patient-derived organoids (PDOs) with TME microbiota would recapitulate the complexity of PDAC paving the way towards a precision oncology treatment-response prediction.

Moving the Needle on Precision Medicine in Pancreatic Cancer.

The management of pancreatic ductal adenocarcinoma (PDAC) has posed a considerable challenge for decades, with incidence and mortality rates almost mirroring each other. Despite this, a deeper understanding of the complex biology inherent to PDAC has provided a roadmap for a more precise approach to treatment. PDAC deficient in homologous recombination repair and mismatch repair is a subgroup that should be identified in the clinic for a targeted approach. In addition, KRAS wild-type PDAC, occurring in approximately 10% of patients, is enriched in highly actionable alterations including fusions, underscoring the importance of integrative germline and somatic sequencing. Comprehensive sequencing efforts over the past decade have documented genomic- and transcriptomic-based classifiers, with the latter emerging as two main subtypes: the classical and basal-like, which are now being evaluated in clinical trials. Together with promising, innovative strategies to target KRAS mutations and their pleotropic effects, a new era of precision medicine in PDAC is on the horizon.

Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response.

Patient-derived organoids (PDO) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping). PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized controlled clinical trial. Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathologic response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment-naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, carbohydrate-antigen 19-9 (CA-19-9), and favorable RECIST imaging response. PDOs established from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC. See related commentary by Zhang et al., p. 3176.

Molecular precision medicine in pancreatic cancer: A single-center experience.

605 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack for treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of them considered as actionable with molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years, with histologically confirmed PDAC, who underwent tumor molecular profiling between 2010 and 2020 in our institution as part of personalized medicine trials. Overall survival was the primary study endpoint (minimal follow-up after molecular profiling, 6 months). Results: Of 115 eligible patients, molecular profiling was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Actionable GAs were found in 29 patients (28%), involving mainly BRCA1/2 (5 [18%]), HER2 (5 [18%]), MTAP (5 [18%]), and FGFR (3 [11%]). Only 12 of these 29 patients (41%, or 10% of the whole population) could receive MTTs accordingly, with a median progression-free survival of 1.6 months. Median OS was 17 months in patients with actionable GAs treated with MTTs (n = 12 [11.8%]), 14 months in patients with actionable GAs not treated with MTTs (n = 17 [16.7%]), and 19 months in patients without actionable GAs treated with standard therapies (n = 73 [71.5%]; p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The longest duration of response with MTTs was observed in patients with BRCA mutations treated with olaparib. Conclusions: Actionable GAs are found in more than the quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study. However, selected GA/MTT duets (e.g., BRCA mutations/olaparib) were associated with better outcome.

Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring.

Simple SummaryNew treatments are urgently needed for pancreatic ductal adenocarcinoma because it is one of the most aggressive and lethal cancers, detected too late and resistant to conventional chemotherapy. Tumors in most patients feature a similar set of core mutations but so far it has not been possible to design a one-fits-all treatment strategy. Instead, efforts are underway to personalize the therapies. To find the treatments that might work the best for each patient, entirely new experimental platforms based on living miniature tumors, organoids, have been developed. We review here the latest international findings in designing personalized treatments pancreatic cancer patients using organoids as testing beds. Our own work adds important clues about how such testing could, and perhaps should, be conducted.Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative approaches are being tested. Organoids can be derived within a short enough time window to allow testing of several anticancer agents, which opens up the possibility for functional precision medicine for pancreatic cancer. At the same time, organoid model systems are being refined to better mimic the cancer, for example, by incorporation of components of the tumor microenvironment. We review some of the latest developments in pancreatic cancer organoid research and in novel treatment design. We also summarize our own current experiences with pancreatic cancer organoid drug sensitivity and resistance testing (DSRT) in 14 organoids from 11 PDAC patients. Our data show that it may be necessary to include a cell death read-out in ex vivo DSRT assays, as metabolic viability quantitation does not capture actual organoid killing. We also successfully adapted the organoid platform for drug combination synergy discovery. Lastly, live organoid culture 3D confocal microscopy can help identify individual surviving tumor cells escaping cell death even during harsh combination treatments. Taken together, the organoid technology allows the development of novel precision medicine approaches for PDAC, which paves the way for clinical trials and much needed new treatment options for pancreatic cancer patients.

EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach.Patients and MethodsFresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS).Results275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia.ConclusionsThis study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population.

MicroRNAs as potential therapeutic targets for pancreatic cancer.

Pancreatic cancer is one of the most aggressive malignancies. The poor prognosis of pancreatic cancer patients is mainly attributed to low diagnostic rate at the early stage, highly aggressive nature coupled with the inadequate efficacy of current chemotherapeutic regimens. Novel therapeutic strategies are urgently needed for pancreatic cancer. MicroRNAs (miRNAs) play an important regulatory role in key processes of cancer development. The aberrant expression of miRNAs is often involved in the initiation, progression, and metastasis of pancreatic cancer. The discovery of tumor suppressor miRNAs provides prospects for the development of a novel treatment strategy for pancreatic cancer. We reviewed recent progress on the understanding of the role of miRNAs in pancreatic cancer, highlighted the efficient application of miRNAs-based therapies for pancreatic cancer in animal models and clinical trials, and proposed future prospects. This review focuses on the promise of integrating miRNAs into the treatment of pancreatic cancer and provides guidance for the development of precision medicine for pancreatic cancer.

Abstract IA-008: The KPC model has helped advance pancreatic cancer therapy: Disagree

Abstract Pancreatic cancer researchers have grappled with the difficulty of reproducing the complex tumor microenvironment which holds the key to improving therapeutic treatments for the disease. For decades, murine models of the disease have underpinned all clinically-relevant pancreatic cancer research and indeed, the transgenic KPC mouse model has been touted as our closest in vivo model to human disease; reproducing disease progression from early PanIN lesions, extensive fibrosis, metastatic spread and chemoresistance. Numerous clinical studies have been initiated based on the work done in this model. However, most of these trials have failed to successfully improve outcomes for pancreatic cancer patients or to even progress beyond phase 2 clinical trials. A/Prof Phillips will argue that the KPC model, while a useful tool to understand pancreatic cancer biology in the laboratory, has had limited clinical impact due to key differences in mouse and human cell biology as well as inherent limitations of the model. Patient-derived 3D tumor models of pancreatic ductal adenocarcinoma (PDAC) have potential to overcome many limitations associated with the KPC model. Human PDAC organoid and whole-tissue explant cultures may hold the key to precision medicine in their ability to predict patient response to existing treatments, to guide translation of new therapies to the clinic in a technique which is both scalable and provides rapid readout 1,2. Furthermore, the ability of the human tumor explant model to retain the multicellular microenvironment of patient tumors provides a powerful tool to study the effects of tumor and stromal targeting agents for pancreatic cancer 3. Coupling this model with the recent explosion of spatial omics techniques also allows us to understand the tumor composition and therapeutic response of individual patient tumors down to the single cell level, negating the need for more homogenous mouse models that require extensive replication and yet make generalized predictions on therapeutic response. Thus, with the advent of these personalized “at-the-bench” 3D human models of pancreatic cancer, perhaps the real question is whether we still require the KPC mouse model?

Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer.

Simple SummaryAmong all types of cancer, Pancreatic Ductal Adenocarcinoma (PDAC) has one of the lowest survival rates, partly due to the failure of current chemotherapeutics. This treatment failure can be attributed to the complicated nature of the tumor microenvironment, where the rich fibro-inflammatory responses can hinder drug delivery and efficacy at the tumor site. Moreover, the high molecular variations in PDAC create a large heterogeneity in the tumor microenvironment among patients. Current in vivo and in vitro options for drug testing are mostly ineffective in recapitulating the complex cellular interactions and individual variations in the PDAC tumor microenvironment, and as a result, they fail to provide appropriate models for individualized drug screening. Organ-on-a-chip technology combined with patient-derived organoids may provide the opportunity for developing personalized treatment options in PDAC.Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of “organ-on-a-chip” approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.

Impact of Endoscopic Ultrasound-Guided Tissue Acquisition on Decision-Making in Precision Medicine for Pancreatic Cancer: Beyond Diagnosis.

Precision medicine in cancer treatment refers to targeted therapy based on the evaluation of biomarkers. Although precision medicine for pancreatic cancer (PC) remains challenging, novel biomarker-based therapies, such as pembrolizumab, olaparib, and entrectinib, have been emerging. Most commonly, endoscopic ultrasound-guided tissue acquisition (EUS-TA) had been used for the diagnosis of PC until now. However, advances in EUS-TA devices and biomarker testing, especially next-generation sequencing, have opened up the possibility of sequencing of various genes even in limited amounts of tissue samples obtained by EUS-TA, and identifying potential genetic alterations as therapeutic targets. Precision medicine benefits only a small population of patients with PC, but biomarker-based therapy has shown promising results in patients who once had no treatment options. Now, the role of EUS-TA has extended beyond diagnosis into decision-making regarding the treatment of PC. In this review, we mainly discuss tissue sampling by EUS-TA for biomarker testing and the current status of precision medicine for PC.

Molecular and Phenotypic Profiling for Precision Medicine in Pancreatic Cancer: Current Advances and Future Perspectives.

Pancreatic cancer is the most common lethal malignancy, with little improvement in patient outcomes over the decades. The development of early detection methods and effective therapeutic strategies are needed to improve the prognosis of patients with this disease. Recent advances in cancer genomics have revealed the genetic landscape of pancreatic cancer, and clinical trials are currently being conducted to match the treatment to underlying mutations. Liquid biopsy-based diagnosis is a promising method to start personalized treatment. In addition to genome-based medicine, personalized models have been studied as a tool to test candidate drugs to select the most efficacious treatment. The innovative three-dimensional organoid culture platform, as well as patient-derived xenografts can be used to conduct genomic and functional studies to enable personalized treatment approaches. Combining genome-based medicine with drug screening based on personalized models may fulfill the promise of precision medicine for pancreatic cancer.

Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer?

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all major cancers. We now know that a ‘one-size-fits-all’ approach when treating PDAC patients does not work, so research has focused on developing personalised treatment strategies based on the biology of each patient’s tumour. However, most of these strategies ignore the presence of the characteristic fibrotic PDAC stroma which can act like a fortress to protect the tumour from chemotherapy and drive its aggressive nature. In this review, we summarise the role of this ‘fortress’ in protecting PDAC from chemotherapy and highlight the need for pre-clinical models that are informing precision medicine to reflect this hallmark feature of PDAC. We also propose the power of ex vivo whole-tissue culture models that mimic the tumour and its surrounding fortress to inform personalised treatment for PDAC.Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and no significant improvement in patient survival has been seen in the past three decades. Treatment options are limited and selection of chemotherapy in the clinic is usually based on the performance status of a patient rather than the biology of their disease. In recent years, research has attempted to unlock a personalised treatment strategy by identifying actionable molecular targets in tumour cells or using preclinical models to predict the effectiveness of chemotherapy. However, these approaches rely on the biology of PDAC tumour cells only and ignore the importance of the microenvironment and fibrotic stroma. In this review, we highlight the importance of the microenvironment in driving the chemoresistant nature of PDAC and the need for preclinical models to mimic the complex multi-cellular microenvironment of PDAC in the precision medicine pipeline. We discuss the potential for ex vivo whole-tissue culture models to inform precision medicine and their role in developing novel therapeutic strategies that hit both tumour and stromal compartments in PDAC. Thus, we highlight the critical role of the tumour microenvironment that needs to be addressed before a precision medicine program for PDAC can be implemented.

Molecular Subtyping and Precision Medicine for Pancreatic Cancer.

Substantial progress in recent years has dramatically increased our knowledge of the molecular basis of cancer, revealing new potential therapeutic targets and paving the way for effective personalised medicine for the treatment of many tumour types. However, pancreatic cancer has been lagging behind in this success and continues to be one of the most lethal solid malignancies. Its molecular heterogeneity and the unselected design of the majority of clinical trials to date can in part explain the reason for our failure to make a significant change in the survival outcomes for patients with pancreatic cancer. A changing paradigm in drug development is required to validate the new molecular taxonomy and to rapidly translate preclinical discovery into clinical trials. Here, we review the molecular subtyping of pancreatic cancer, the challenges in identifying effective treatment regimens according to defined low-prevalence molecular subgroups and we illustrate a new model of translational therapeutic development that was established in the U.K. (Precision-Panc) as a potentially effective solution to improve outcomes for patients with pancreatic cancer.

Precision medicine for pancreatic cancer: real-world evidence from the Know Your Tumor programme

Precision medicine for pancreatic cancer: real-world evidence from the Know Your Tumor programme

Precision medicine for pancreatic cancer in national health care system: The initial Precision-Panc experience

Precision medicine for pancreatic cancer in national health care system: The initial Precision-Panc experience