Skip to main content

mouse model

Study Suggests Repurposed Drugs Might Treat Aggressive Lung Cancer

Posted on by

Small cell lung cancer cells
Caption: Small cell lung cancer cells (red) spreading via blood vessels (white) from the lung to the liver of a genetically-engineered mouse model.
Credit: Leanne Li, Koch Institute at MIT

Despite continued progress in treatment and prevention, lung cancer remains our nation’s leading cause of cancer death. In fact, more Americans die of lung cancer each year than of breast, colon, and prostate cancers combined [1,2]. While cigarette smoking is a major cause, lung cancer also occurs in non-smokers. I’m pleased to report discovery of what we hope will be a much-needed drug target for a highly aggressive, difficult-to-treat form of the disease, called small cell lung cancer (SCLC).

Using gene-editing technology to conduct a systematic, large-scale search for druggable vulnerabilities in certain types of cancer cells grown in lab dishes, NIH-funded researchers recently identified a metabolic pathway that appears to play a key role in SCLC. What makes this news even more encouraging is drugs that block this pathway already exist. That includes one in clinical testing for other types of cancer, and another that’s FDA-approved and has been safely used for more than 20 years to treat people with rheumatoid arthritis.

The new work comes from the lab of Tyler Jacks, Massachusetts Institute of Technology (MIT), Cambridge. The Jacks lab, which is dedicated to understanding the genetic events that lead to cancer, develops mouse models engineered to carry the same genetic mutations that turn up in human cancers.

In work described in Science Translational Medicine, the team, co-led by Leanne Li and Sheng Rong Ng, applied CRISPR gene-editing tools to cells grown from some of their mouse models. Aiming high in terms of scale, researchers used CRISPR to knock out systematically, one by one, each of about 5,000 genes in cells from the SCLC mouse model, as well in cells from mouse models of other types of lung and pancreatic cancers. They looked to see what gene knockouts would slow down or kill the cancer cells, because that would be a good indication that the protein products of these genes, or the pathways they mediated, would be potential drug targets.

Out of those thousands of genes, one rose to the top of the list. It encodes an enzyme called DHODH (dihydroorotate dehydrogenase). This enzyme plays an important role in synthesizing pyrimidine, which is a major building block in DNA and RNA. Cytosine and thymine, the C and T in the four-letter DNA code, are pyrimidines; so is uracil, the U in RNA that takes the place of T in DNA. Because cancer cells are constantly dividing, there is a continual need to synthesize new DNA and RNA molecules to support the production of new daughter cells. And that means, unlike healthy cells, cancer cells require a steady supply of pyrimidine.

It turns out that the SCLC cells have an unexpected weakness relative to other cancer cells: they don’t produce as much pyrimidine. As a result, the researchers found blocking DHODH left the cells short on pyrimidine, leading to reduced growth and survival of the cancer.

This was especially good news because DHODH-blocking drugs, including one called brequinar, have already been tested in clinical trials for other cancers. In fact, brequinar is now being explored as a potential treatment for acute myeloid leukemia.

Might brequinar also hold promise for treating SCLC? To explore further, the researchers looked again to their genetic mouse model of SCLC. Their studies showed that mice treated with brequinar lived about 40 days longer than control animals. That’s a significant survival benefit in this system.

Brequinar treatment appeared to work even better when combined with other approved cancer drugs in mice that had SCLC cells transplanted into them. Further study in mice carrying SCLC tumors derived from four human patients added to this evidence. Two of the four human tumors shrunk in mice treated with brequinar.

Of course, mice are not people. But the findings suggest that brequinar or another DHODH blocker might hold promise as a new way to treat SCLC. While more study is needed to understand even better how brequinar works and explore potentially promising drug combinations, the fact that this drug is already in human testing for another indication suggests that a clinical trial to explore its use for SCLC might happen more quickly.

More broadly, the new findings show the promise of gene-editing technology as a research tool for uncovering elusive cancer targets. Such hard-fought discoveries will help to advance precise approaches to the treatment of even the most aggressive cancer types. And that should come as encouraging news to all those who are hoping to find new answers for hard-to-treat cancers.

References:

[1] Cancer Stat Facts: Lung and Bronchus Cancer (National Cancer Institute/NIH)

[2] Key Statistics for Lung Cancer (American Cancer Society)

[3] Identification of DHODH as a therapeutic target in small cell lung cancer. Li L, Ng SR, Colón CI, Drapkin BJ, Hsu PP, Li Z, Nabel CS, Lewis CA, Romero R, Mercer KL, Bhutkar A, Phat S, Myers DT, Muzumdar MD, Westcott PMK, Beytagh MC, Farago AF, Vander Heiden MG, Dyson NJ, Jacks T. Sci Transl Med. 2019 Nov 6;11(517).

Links:

Small Cell Lung Cancer Treatment (NCI/NIH)

Video: Introduction to Genome Editing Using CRISPR Cas9 (NIH)

Tyler Jacks (Massachusetts Institute of Technology, Cambridge)

NIH Support: National Cancer Institute


Creative Minds: Taking Aim at Adverse Drug Reactions

Posted on by

Sherrie Divito

Sherrie Divito

As a practicing dermatologist, Sherrie Divito sees lots of patients each week at Brigham and Women’s Hospital, Boston. She also sees lots of research opportunities. One that grabbed her attention is graft-versus-host disease (GvHD), which can arise after a bone-marrow transplant for leukemia, lymphoma, or various other diseases. What happens is immune cells in the donated marrow recognize a transplant patient’s body as “foreign” and launch an attack. Skin is often attacked first, producing a severe rash that is a harbinger of complications to come in other parts of the body.

But Divito saw something else: it’s virtually impossible to distinguish between an acute GvHD-caused rash and a severe skin reaction to drugs, from amoxicillin to carbamazepine. In her GvHD studies, Divito had been researching a recently identified class of immune cell called tissue-resident memory T (Trm) cells. They remain in skin rather than circulating in the bloodstream. The clinical similarities made Divito wonder whether Trm cells may also help to drive severe skin allergies to drugs.

Divito has received a 2016 NIH Director’s Early Independence Award to find out. If correct, Divito will help not only to improve the lives of thousands of people with GvHD, but potentially benefit the millions of other folks who experience adverse reactions to drug.


DNA and the Roots of Hair Roots

Posted on by

An Asian family (adult male and female and two adolescents, male and female) sitting around a coffee table playing a board game

Researchers have discovered one genetic recipe for this family’s thick dark hair.
Source: National Cancer Institute, NIH; Bill Branson, photographer.

It’s intriguing to find the roots of physical traits: skin color, height, and those weird tufts of hair on Uncle Mike’s ears. We’re all curious to know why we look the way we do. But new technologies are allowing us to discover the precise genetic roots of human traits that vary across the world. Variations in our DNA have helped us resist diseases and adapt to different climates and foods, enabling us to colonize just about every environment on the planet.

Recent studies have pinpointed variations responsible for lighter skin in Northern climates (such as SLC24A5 [1]) and the ability to tolerate milk sugar (lactose) in adulthood [2]. But a new NIH-funded study of a gene variant that arose in China adds a fascinating wrinkle—the use of a mouse model to help understand a potential human advantage [3]. (Regular readers will note that last week in this space I wrote about how mouse models could sometimes be misleading—this week the mouse is a champion!)