From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer

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Abstract

Improvements in the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have lagged behind advances made in the treatment of many other malignancies over the past few decades. For most patients with PDAC, cytotoxic chemotherapy remains the mainstay of treatment. For patients with resectable disease, modified 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (mFOLFIRINOX) is the standard-of-care adjuvant therapy, although data from several randomized trials have shown improved outcomes with neoadjuvant treatment strategies. For patients with advanced-stage or metastatic disease, comprehensive genomic profiling has revealed several potentially actionable alterations in small subsets of patients and the feasibility of implementing such strategies is beginning to be confirmed. Novel therapies targeting certain aberrations, most notably BRCA1/2 mutations, mismatch repair (MMR) deficiencies or NTRK1-3 fusions, have shown considerable activity in clinical trials, and larotrectinib, entrectinib and pembrolizumab have received FDA approval for the treatment of patients with tumours harbouring NTRK fusions and MMR deficiencies, respectively, regardless of primary tumour histology. In this Review, we describe the available data on the activity of these and other agents in patients with PDAC. Our discussion is structured according to the acronym 'PRIME' to organize the various treatment strategies currently undergoing evaluation in clinical trials: Pathway inhibition, alteration of DNA Repair pathways, Immunotherapy, cancer Metabolism and targeting the Extracellular tumour microenvironment.

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Identification of pancreatic cancer stem cells.

Chenwei Li, David G Heidt, Piero Dalerba … (2007)

Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.

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Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

Richard A Moffitt, Raoud Marayati, Elizabeth Flate … (2015)

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical.

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Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

(2017)

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.