Mining the genomes of exceptional responders

Chang, David K.; Grimmond, Sean M.; Evans, T.R. Jeff; Biankin, Andrew V.

doi:10.1038/nrc3723

Cited by 37 publications

(28 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Accumulating case reports and evidence from exceptional responders are identifying candidate molecular targets for current and novel therapeutics in PDAC (39). Perhaps the most promising, at present, is targeting DNA damage response (DDR) deficiency.…”

Section: Targeting Ddr Deficiencymentioning

confidence: 99%

See 1 more Smart Citation

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Dreyer

Chang

Bailey

et al. 2017

Clinical Cancer Research

Self Cite

147

114

View full text Add to dashboard Cite

Pancreatic cancer has become the 3 rd leading cause of cancer death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet, only 20% will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers, and beyond that a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient sub-groups. With the development of next generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection.Incorporating pre-clinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.3

show abstract

Section: Targeting Ddr Deficiencymentioning

confidence: 99%

“…Exceptional responders to platinum therapy are well documented, yet biomarkers of response require testing in prospective clinical trials (9,39). BRCA1 and BRCA2 germline carriers are known to respond to platinums and PARP-inhibitors in multiple tumor types including early data for PDAC (41,48).…”

Section: Targeting Ddr Deficiencymentioning

confidence: 99%

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Dreyer

Chang

Bailey

et al. 2017

Clinical Cancer Research

Self Cite

147

114

View full text Add to dashboard Cite

show abstract

“…Adaptive (nongenetic or regulatory) responses, such as increased expression of the therapeutic target or activation of compensatory pathways, can also influence drug efficacy over time (1). Despite the widespread prevalence of tumor resistance, which in many cases may be due to drug resistance, many oncologists have noted occasional dramatic responses in patients, whom they referred to informally as "exceptional responders" (2). However, despite the many potential biomarkers and our increasingly sophisticated understanding of the molecular phenotype of the tumor cell, we cannot predict exceptional responders.…”

mentioning

confidence: 99%

Hippo pathway mediates resistance to cytotoxic drugs

Gujral

Kirschner

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Chemotherapy is widely used for cancer treatment, but its effectiveness is limited by drug resistance. Here, we report a mechanism by which cell density activates the Hippo pathway, which in turn inactivates YAP, leading to changes in the regulation of genes that control the intracellular concentrations of gemcitabine and several other US Food and Drug Administration (FDA)-approved oncology drugs. Hippo inactivation sensitizes a diverse panel of cell lines and human tumors to gemcitabine in 3D spheroid, mouse xenografts, and patient-derived xenograft models. Nuclear YAP enhances gemcitabine effectiveness by down-regulating multidrug transporters as well by converting gemcitabine to a less active form, both leading to its increased intracellular availability. Cancer cell lines carrying genetic aberrations that impair the Hippo signaling pathway showed heightened sensitivity to gemcitabine. These findings suggest that "switching off" of the Hippo-YAP pathway could help to prevent or reverse resistance to some cancer therapies.drug resistance | Hippo pathway | gemcitabine | cell density | cancer

show abstract

“…Upon reviewing other cases analysed by APGI, there are several examples of exceptional responders to platinums in the DNA damage repair pathway genotypes (10). Given the patient's family history of pancreatic cancer and personal history of breast cancer, the PALB2 mutation is almost certainly pathogenic and genetic counselling for her family has been recommended.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic PALB2 mutation in metastatic pancreatic adenocarcinoma and neuroendocrine tumour: A case report

Chan

Clarke

Gill

et al. 2015

Molecular and Clinical Oncology

View full text Add to dashboard Cite

Abstract. Adenocarcinoma of the pancreas is an aggressive malignancy with poor prognosis. Pancreatic neuroendocrine tumours (PNET) comprise ~3% of primary pancreatic neoplasms and they are more heterogeneous in their histological character and outcome. This is the case report of a 73-year-old female patient with synchronously diagnosed pancreatic adenocarcinoma and PNET, which is likely associated with a pathogenic partner and localizer of breast cancer 2, early onset (PALB2) mutation. The potential pathogenic significance of PALB2 and its association with various malignancies were investigated and the potential role of PALB2 in conferring sensitivity to chemotherapeutic agents, such as mitomycin C and cisplatin, was discussed. This case report highlights the significance of ongoing research into the molecular pathogenesis of pancreatic cancer, which may help guide the selection of optimal treatments for this disease, as well as the need for ongoing study of PALB2 as a possible predictive marker of response to DNA-damaging agents.

show abstract

Mining the genomes of exceptional responders

Cited by 37 publications

References 6 publications

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Hippo pathway mediates resistance to cytotoxic drugs

Pathogenic PALB2 mutation in metastatic pancreatic adenocarcinoma and neuroendocrine tumour: A case report

Contact Info

Product

Resources

About