Frustration often leads to innovation. Thomas Edison himself called discontent the “first necessity of progress.”
For Nicholas Navin, Ph.D., it drove him to pioneer a technique that has revolutionized the way researchers are able to study cancer.
Understanding evolution within cancer cells is a longtime interest for the associate professor of Genetics and Bioinformatics. In other words, how does a single, tiny cell with a few mutations grow uncontrollably into devastating disease?
To answer that question, Navin needed to analyze DNA from individual cancer cells, but that proved easier said than done. Traditional methods weren’t useful because they relied on mixtures of millions of cells.
“I spent most of my graduate studies slicing up tumors into multiple regions and doing genomic profiling,” Navin says. “And no matter how much I sliced up the tumor, I would always deal with a mixed population. So that was very frustrating.”
Analyzing DNA from a single cell
A tumor can contain billions of cells, many of which aren’t cancerous, with diverse genetic profiles. The mixed samples Navin was able to collect did not provide clear answers, so he decided to devise a better technique.
In 2011, as a postdoctoral fellow in Cancer Genetics at Cold Spring Harbor Laboratory in New York, Navin published one of the first methods for analyzing DNA from a single cell. The technique, now widely used, involves meticulously isolating an individual tumor cell, amplifying its genetic material to provide enough sample for analysis, and analyzing the DNA for anomalies.
In just a few days, this can be repeated for thousands and thousands of individual cells, creating a picture of the cell diversity within a tumor and how they interact – known as the tumor architecture. Understanding biology at this level can provide valuable insights into cancer growth and progression, particularly in the disease’s early stages.
“You can trace back all the events that occurred up to that one single cell that started the tumor,” Navin says. “That is very useful for studying things like invasion, metastasis and therapy resistance.”
Moon shots collaborations
Navin is confident this technique will benefit both patients and researchers. Through MD Anderson’s Moon Shots Program™, he is collaborating with clinicians across several cancer types to more rapidly incorporate the use of single-cell analysis, with the goal of improving care.
The ability to work with expert cancer doctors and pathologists together under one roof, along with access to a large volume of patient samples, provides an unparalleled advantage for identifying and developing clinical applications, Navin explains.
Through those collaborations, it has become clear that single-cell analysis is extremely useful for both studying a large number of individual tumor cells, and in cases where very few cells are available for study.
Targeting AML recurrence
For example, Navin is working with Michael Andreeff, M.D., Ph.D., and Marina Konopleva, M.D., Ph.D., both professors of Leukemia, and the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot™, to study a very rare collection of cells that lead to relapse in patients with acute myeloid leukemia (AML).
In certain AML patients, a small subset of leukemia cells survives initial treatment with chemotherapy.
This condition, called minimal residual disease, is associated with recurrence and poor prognosis. However, these cells only represent approximately one out of 10,000 cells in the bone marrow, making them difficult to study.
“There is no way to identify these cells before treatment,” Andreeff says. “That’s why it’s so important to isolate these very rare cells after treatment. This technique is unique and extremely valuable in doing that. It also shows the value and benefit provided by collaborations within the Moon Shots Program.”
By using single-cell analytics, the team is able to learn about genetic mutations, active signaling pathways and proteins on the cell-surface, all of which may be useful for choosing or developing new therapies to target this group of resistant cells.
Improving outcomes for prostate cancer patients
Similarly, Navin is partnering with Amado Zurita-Saavedra, M.D., and Ana Aparicio, M.D., both associate professors of Genitourinary Medical Oncology, through the Prostate Cancer Moon Shot™ to study the evolution of prostate cancer cells in response to different treatments such as hormonal therapy or chemotherapy.
They are using single-cell analysis to study circulating tumor cells in the blood of prostate tumors, and metastasized cells taken from bone marrow. With Navin’s methodology, the team is able to analyze these limited samples and observe changes in a patient’s tumor throughout the course of treatment, without the need for invasive biopsies.
“We want to learn what it is that’s being enriched and what it is that’s disappearing from individual tumors in the context of life-prolonging therapies for prostate cancer, in order to make it more clinically relevant,” Zurita-Saavedra says. “Our end goal is to be able to anticipate therapy response in our patients.”
Understanding the tumor architecture during therapy will help predict response to available treatments, and help guide clinicians in choosing one with a higher probability of success, he explains.
Through these and other collaborations, Navin continues to expand on the clinical possibilities for single-cell analytics, which include early detection of cancer using blood samples, non-invasive tumor monitoring and the analysis of patient samples that are too small to be processed with standard methods. He also is working with the Moon Shots Program to incorporate the use of single-cell analysis more broadly at MD Anderson.
From frustration to innovation, his goal now is to bring his technique to the labs of many more researchers and clinicians at MD Anderson in order to revolutionize patient care.
“Single-cell analysis will be critical as we enter the era of precision medicine. Dr. Navin’s work has already begun to provide insight into how a tumor’s genotype [and] phenotype evolve in response to therapeutic interventions.”