Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers

From Science

1. David T. Ting¹,*, 
2. Doron Lipson²,*, 
3. Suchismita Paul¹, 
4. Brian W. Brannigan¹ , 
5. Sara Akhavanfard¹, 
6. Erik J. Coffman¹,
7. Gianmarco Contino¹, 
8. Vikram Deshpande¹, 
9. A. John Iafrate¹, 
10. Stan Letovsky², 
11. Miguel N. Rivera¹, 
12. Nabeel Bardeesy¹,
13. Shyamala Maheswaran¹ and 
14. Daniel A. Haber¹,³,^†

Satellite repeats in heterochromatin are transcribed into noncoding RNAs that have been linked to gene silencing and maintenance of chromosomal integrity. Using digital gene expression analysis, we show that these transcripts are greatly overexpressed in mouse and human epithelial cancers. In 8 of 10 mouse pancreatic ductal adenocarcinomas (PDAC), pericentromeric satellites accounted for a mean 12% (range 1 to 50%) of all cellular transcripts, a mean 40-fold increase over normal tissue. In 15/15 human PDACs, alpha satellite transcripts were most abundant and HSATII transcripts were highly specific for cancer. Similar patterns were observed in cancers of lung, kidney, ovary, colon, and prostate. Derepression of satellite transcripts correlated with overexpression of the LINE-1 retrotransposon and with aberrant expression of neuroendocrine-associated genes proximal to LINE-1 insertions. The overexpression of satellite transcripts in cancer may reflect global alterations in heterochromatin silencing and could potentially be useful as a biomarker for cancer detection.

Are we ready for personalized cancer treatments?

I'm not sure this has the potential to become the standard of care anytime soon. However the challenge is there and most likely worth a try.

What are the current limiting factors for this approach?

- Cost (but despite the fact it is so evident, I believe it is not the main one)

- Trial Design for personalized therapies; how can we prove those therapies are effective?

- Facilities, how many cancer centers are TRULY ready to accomodate routine processing and biobanking of primary cell lines or xenograft?

- What's first? Whole exome seq or In Vitro drug response?

Mol Cancer Ther. 2010 Dec 6. [Epub ahead of print]

Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer.

Villarroel MC, Rajesh Kumar NV, Garrido-Laguna I, De Jesus-Acosta A, Jones S, Maitra A, Hruban RH, Eshleman JR, Klein AP, Laheru D, Donehower RC, Hidalgo M.

1GI Oncology, The Sidney Kimmel Cancer Center at Johns Hopkins.

Abstract

Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, based on the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected based on its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long lasting (36+ months) tumor response. Global geneomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer, the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customize therapy, tailored to the genetic environment of patient's tumor and identification of a new biomarker of drug response in a lethal cancer.

Rethinking the scientific method: newyorker.com

Rethinking the scientific method: newyorker.com

The Truth Wears Off - Is there something wrong with the scientific method?

Is long-term solitary confinement torture?: newyorker.com

Is long-term solitary confinement torture?: newyorker.com

The United States holds tens of thousands of inmates in long-term solitary confinement. Is this torture?

by Atul Gawande

No survival benefit for Neoadjuvant Chemotherapy Compared With Surgery Alone for Locally Advanced Cancer of the Stomach and Cardia, results from EORTC trial 40954

Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. A Randomized EORTC trial (40954) examined the value of purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines. Authors found a significantly increased R0 (radical, no tumor left) resection rate in the preoperative chemotherapy group, but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including esophagogastric junction (AEG) and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).

Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study

Cetuximab plus GEMOX was well tolerated and had encouraging antitumour activity, leading to secondary resection in a third of patients. These findings warrant further study of cetuximab plus GEMOX in a large randomised trial.

FOLFIRINOX: a new standard treatment for advanced pancreatic cancer?

by Richard Kim on Lancet oncology

Pancreatic cancer is still a lethal disease because of its tendency to undergo early subclinical metastasis to the regional lymph nodes and liver. Gemcitabine has been the standard chemotherapy for metastatic pancreatic cancer for many years on the basis of a phase 3 trial showing its clinical benefit over fluorouracil;1 however, the median survival was only 5·6 months and response rate only 5%. Since then, many trials have been done with gemcitabine being the backbone of the doublet or triplet regimens to improve overall outcome in patients.