演題抄録

基調講演

開催概要
開催回
第51回・2013年・京都
 

Pancreatic Cancer: From Molecular Understanding to Personalized Treatment

演題番号 : KL-8

[筆頭演者]
Manuel Hidalgo:1 

1:Centro Nacional de Investigaciones Oncologicas, Madrid, Spain

 

Pancreatic cancer remains one of the most deadly cancers. Over the last few years, the genomic landscape of pancreatic cancer as well as precursor pancreatic cancer lesions have been deciphered in great depth. These studies show that PDA develops as the consequence of accumulation of mutations in key oncogenes and tumour suppressor genes. The disease, once established, is characterized by high complexity, heterogeneity and genomic instability. Despite this facts, some patients harbour actionable mutations which targeting has resulted in significant clinical benefit. Indeed, one of the most active areas of research in PDA is the development of strategies and approaches to personalize the treatment of patients. This is a complex field that can be tackle from many complementary angles. Our group has been interested in using patient derive xenogaft (PDX) models, aka Avatar mouse models, to guide cancer treatment. A piece of freshly collected tumour is implanted in immunodeficient mouse models, expanded, treated with different anticancer agents alone and in combination to select the most effective drug/regimen to treat the patient cancer. Our data show that the approach is highly predicted but, because of complexity and cost issues, not widely applicable to clinical practice at the present stage. To solve some of these limitations we are working on different aspects. One area is technological development to increase the take rate of tumours and to speed time to engraftment and expansion time. Currently, these figures are approximately 60-80 % and 5-7 months. Studies are in progress to optimize this aspect. Another key question is the selection of agents, both alone and in combination, to be tested in the model. In this regard, it is important to integrate biomarker assessment in the tumour to pre-select a series of treatment candidates that can then be tested in the PDX models. To this end, we have now integrated next generation sequencing and assessment of copy number variation in patient’s tumour. These studies provide us with an unbiased overview of the tumour genomic landscape. From this data, using different bioinformatics and biological methods we extract the most relevant drug targets that are then bench tested against the patient Avatar mouse model to select the most effective treatment.

Another area of great interest in PDA therapeutics is the cancer microenvironment. PDA is known for a flourish cancer stroma composed of extracellular matrix and cells including inflammatory, immune and cancer associate fibroblast. Strategies aiming to eliminate the cancer stroma with agents such as hyaluronidase and Hh inhibitors among others have received substantial attention. nabPTX, an agent proposed to target SPARC, one of the key elements in the PDA stroma, has shown improvement in overall survival and is likely to received regulatory approval for this disease. Agents in this category will also be reviewed.

Finally, strategies to target the cancer stem cell will be presented. Laboratory studies have shown the presence of a small percentage of cells in PDA tumours with stem properties. These cells can be identified by membrane markers and are considered to be resistant to chemotherapy and radiotherapy. It is possible, that CSC is responsible for cancer failure after definitive chemotherapy and radiotherapy and there is significant interest in developing agents to selectively eliminate these cells.

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