Pancreas cancer liquid biopsy flows from blood-borne packets of tumor genes

December 17, 2015

Pancreatic cancer tumors spill their molecular secrets into the blood stream, shedding their complete DNA and RNA wrapped inside protective lipid particles that make them ripe for analysis with a liquid biopsy, researchers at The University of Texas MD Anderson Cancer Center report online at the Annals of Oncology.

The team conducted whole genome, whole exome and gene expression analysis of tumors in three patients using DNA and RNA found inside exosomes circulating in their blood or other liquid biospecimens.

"Analysis of exosomal DNA and RNA allows us to do everything you can do off a direct biopsy of tumor tissue," said senior author Anirban Maitra, M.B.B.S., professor of Pathology and director of MD Anderson's Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research.

The research was conducted under MD Anderson's Moon Shots Program to accelerate development of clinical and prevention advances from scientific knowledge. Maitra is co-leader of the Pancreatic Cancer Moon Shot, one of 12 in the program.

The proof of principle study opens the door to validation studies in multiple tumor types of a liquid biopsy that could be used to determine prognosis, guide targeted therapy and monitor treatment.

Meeting pancreatic biopsy challenge

Maitra and colleagues detected a variety of cancer-derived biomarkers, including genetic mutations, insertions, deletions, copy number profiles and gene fusions that can act as neoantigens - new targets for the immune system. Potentially treatable mutations, including BRCA2 and NOTCH1, were identified.

"A comprehensive liquid biopsy would meet one of the major challenges of characterizing pancreatic cancer and other cancers deep in the body," Maitra said. "These tumors are hard to access, even using needle or core biopsies, so getting enough tissue to enable a full next-generation sequencing is difficult."

Other liquid biopsies under development rely mainly on cell-free DNA found circulating in the blood. Unprotected DNA in the blood is chopped up by enzymes, so cell-free DNA allows some genomic analysis, Maitra said, but not whole genome or whole exome sequencing.

Cell-free RNA is even more easily destroyed in the blood. Exosomes are membrane balls that protect the DNA and the RNA cargo inside from destruction, preserving high-quality samples.

Analyzing gene expression

"Full RNA sequencing is important because genome sequencing tells you what genes are altered, while analysis of RNA tells you what abnormal genes are actually being expressed," he said. "Shed exosomes allow us to do matched DNA and RNA simultaneously in liquid biopsies at a resolution that is not amenable with cell-free approaches."

Common clinical practice now calls for only a pretreatment biopsy in deeply located tumors at presentation. Conducting biopsies during treatment would more closely monitor therapy success or failure and help researchers better understand how the cancer genome evolves in response to treatment.

"Tumors continuously evolve during therapy. New changes, new pathways, new mutations show up," Maitra said. Payers don't usually cover multiple biopsies. "Now you can bypass the need for tissue and get the full genome, exome and transcriptome from a vial of blood," Maitra said.

Exosomes may actually paint a more complete picture of a tumor's genomic diversity because all genetic mutations present in primary and metastatic tumors would flow into a liquid biopsy via the exosomes, the researchers noted. Sampling part of a tumor might only capture mutations in that area and not reflect its overall genomic diversity.

Exosomes were isolated from blood samples in two patients and also from pleural fluid in a patient who had lung metastases. Whole genome sequencing covered up to 91 percent of the human genome while exome sequencing of only the protein-coding genes covered 95 to 99 percent.

Validation in larger sample, more cancers

Co-author Ignacio Wistuba, M.D., chair of Translational Molecular Pathology, is working with Maitra and other investigators at MD Anderson to develop an assay to capture exosomes and validate the approach across other "visceral" (deeply located) cancers.

Maitra and Wistuba plan to work with other cancer moon shots initially, with the ultimate goal of developing a clinical-quality liquid biopsy for use institutionwide.

"We'll validate in a larger population cohort and correlate our findings with patient outcomes," Wistuba said. "There's no clinical application yet, we're early in development, but it's very exciting."
-end-
Maitra holds the Sheikh Khalifa Bin Zayed Al Nahyan Distinguished University Chair. The Annals of Oncology is the official publication of the European Society for Medical Oncology.

Co-authors with Maitra and Wistuba are co-first authors Francis San Lucas, Ph.D., of Translational Molecular Pathology; Kelvin Allenson, M.D., of Surgical Oncology; and Vincent Bernard, of Pathology, who is also a graduate student in The University of Texas Graduate School of Biomedical Sciences, jointly operated by MD Anderson and The University of Texas Health Science Center at Houston; and Hector Alvarez, M.D., Ph.D., who is scientific manager of the Liquid Biopsy platform in the pancreatic cancer research center and co-senior author of the publication. Other co-authors include Jonathan Castillo, Ph.D., Dong Kim, M.D., and Kristen Ellis of Pathology; Donghui Li, Ph.D., Robert Wolff, M.D., and Gauri Varadhachary, M.D., M.B.B.S, of Gastrointestinal Medical Oncology; Matthew Katz, M.D. of Surgical Oncology, and Eric Ehli, Ph.D., Gareth Davies, Ph.D., and Jason Petersen, Ph.D., of Avera Institute for Human Genetics, Sioux Falls, S.D.

This research was funded by MD Anderson's Pancreatic Cancer Moon Shot, the Sheikh Ahmed Pancreatic Cancer Research Center, grants from the National Cancer Institute of the National Institutes of Health (5T32CA009599-27, R01CA113669, U01CA196403, U01DK108328, P30CA016672), MD Anderson's NCI Cancer Center Support Grant (CA16672) for the High Resolution Electron Microscopy Facility, the Translational Molecular Pathology Fellowship at MD Anderson; and the Cancer Prevention and Research Institute of Texas.

University of Texas M. D. Anderson Cancer Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.