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Recent advances in precision medicine for pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide. Although advances in systemic chemotherapy for PDAC have improved survival outcomes for patients with the disease, chemoresistance is a major treatment issue for unselected PDAC patient populations. The existence of heterogeneity caused by a mixture of tumor cells and stromal cells produces chemoresistance and limits the targeted therapy of PDAC. Advances in precision medicine for PDACs according to the genetics and molecular biology of this disease may represent the next alternative approach to overcome the heterogeneity of different patients and improve survival outcomes for this poor prognostic disease. The genetic alteration of PDAC is characterized by four genes that are frequently mutated (KRAS, TP53, CDKN2A, and SMAD4). Furthermore, several genetic and molecular profiling studies have revealed that up to 25% of PDACs harbor actionable alterations. In particular, DNA repair dysfunction, including cases with BRCA mutations, is a causal element of sensitivity to platinum-based anti-cancer agents and poly-ADP ribose polymerase (PARP) inhibitors. A deep understanding of the molecular and cellular crosstalk in the tumor microenvironment helps to establish scientifically rational treatment strategies for cancers that show specific molecular profiles. Here, we review recent advances in genetic analysis of PDACs and describe future perspectives in precision medicine according to molecular subtypes or actionable gene mutations for patients with PDAC. We believe the breakthroughs will soon emerge to fight this deadly disease.

SUBMITTER: Hayashi H

PROVIDER: S-EPMC8316748 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Applied precision medicine in metastatic pancreatic ductal adenocarcinoma.

Project description:BackgroundMetastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options.MethodsIn this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization.ResultsIn total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n = 40; 80%), TP53 (n = 29; 58%), CDKN2A (n = 8; 16%), SMAD4 (n = 4; 8%), and NOTCH1 (n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1-PIK3CA and EIF3E-RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus (n = 3), pembrolizumab (n = 3), palbociclib (n = 2), nintedanib (n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each.Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months.ConclusionBased on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.

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Pancreatic ductal adenocarcinoma in the era of precision medicine.

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Project description:Patients with pancreatic ductal adenocarcinoma (PDA) have a poor prognosis despite new treatments; approximately 7% survive for 5 years. Although there have been advances in systemic, primarily cytotoxic, therapies, it has been a challenge to treat patients with PDA using targeted therapies. Sequence analyses have provided a wealth of information about the genetic features of PDA and have identified potential therapeutic targets. Preclinical and early-phase clinical studies have found specific pathways could be rationally targeted; it might also be possible to take advantage of the genetic diversity of PDAs to develop therapeutic agents. The genetic diversity and instability of PDA cells have long been thought of as obstacles to treatment, but are now considered exploitable features. We review the latest findings in pancreatic cancer genetics and the promise of targeted approaches in PDA therapy.

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Project description:Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies among all cancers. Despite curative intent, surgery and the use of standard cytotoxic chemotherapy and radiation therapy, PDAC remains treatment-resistant. In recent years, more contemporary treatment modalities such as immunotherapy via checkpoint inhibition have shown some promise in many other malignancies, yet PDAC still eludes an effective curative treatment. In investigating these phenomena, research has suggested that the significant desmoplastic and adaptive tumor microenvironment (TME) of PDAC promote the proliferation of immunosuppressive cells and act as major obstacles to treatment efficacy. In this review, we explore challenges associated with the treatment of PDAC, including its unique immunosuppressive TME. This review examines the role of surgery in PDAC, recent advances in surgical approaches and surgical optimization. We further focus on advances in immunotherapeutic approaches, including checkpoint inhibition, CD40 agonists, and discuss promising immune-based future strategies, such as therapeutic neoantigen cancer vaccines as means of overcoming the resistance mechanisms which underly the dense stroma and immune milieu of PDAC. We also explore unique signaling, TME and stromal targeting via novel small molecule inhibitors, which target KRAS, FAK, CCR2/CCR5, CXCR4, PARP and cancer-associated fibroblasts. This review also explores the most promising strategy for advancement in treatment of pancreatic cancer by reviewing contemporary combinatorial approaches in efforts to overcome the treatment refractory nature of PDAC.

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with an extremely poor prognosis and low survival rate. Due to its inconspicuous symptoms, PDAC is difficult to diagnose early. Most patients are diagnosed in the middle and late stages, losing the opportunity for surgery. Chemotherapy is the main treatment in clinical practice and improves the survival of patients to some extent. However, the improved prognosis is associated with higher side effects, and the overall prognosis is far from satisfactory. In addition to resistance to chemotherapy, PDAC is significantly resistant to targeted therapy and immunotherapy. The failure of multiple treatment modalities indicates great dilemmas in treating PDAC, including high molecular heterogeneity, high drug resistance, an immunosuppressive microenvironment, and a dense matrix. Nanomedicine shows great potential to overcome the therapeutic barriers of PDAC. Through the careful design and rational modification of nanomaterials, multifunctional intelligent nanosystems can be obtained. These nanosystems can adapt to the environment's needs and compensate for conventional treatments' shortcomings. This review is focused on recent advances in the use of well-designed nanosystems in different therapeutic modalities to overcome the PDAC treatment dilemma, including a variety of novel therapeutic modalities. Finally, these nanosystems' bottlenecks in treating PDAC and the prospect of future clinical translation are briefly discussed.

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Project description: Not available

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with increasing incidence and mortality. More than half of PDAC patients develop metastases, with the liver being the most common site. Patients with pancreatic ductal adenocarcinoma with liver metastases (PCLM) have a very limited scope for surgery due to aggressive tumor behavior and poor prognosis. However, with the improvements in preoperative systemic therapy and perioperative outcomes, an increasing number of patients are being considered for surgical management. However, the best choice of surgical treatment and criteria for selecting suitable PCLM patients who may benefit from surgical treatment remains controversial. Palliative local treatments, such as ablation, locoregional chemotherapy, and brachytherapy, which are less invasive and have fewer contraindications and complications, are the preferred alternatives to surgery. The present study reviews the advances in the management of PCLM, with focus on resection and local therapies.

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