Researchers identify new target, develop new drug for cancer therapies

September 20, 2017, Perelman School of Medicine at the University of Pennsylvania
A model of Penn's new approach using DQ611 to target PPT1, which inhibits both mTOR and autophagy. Credit: Penn Medicine

Opening up a new pathway to fight cancer, researchers at the University of Pennsylvania have found a way to target an enzyme that is crucial to tumor growth while also blocking the mechanism that has made past attempts to target that enzyme resistant to treatment. Researchers were able to use this finding to develop a drug that successfully inhibits tumor growth of melanoma as well as pancreatic and colorectal cancer in mice. The journal Cancer Discovery published the findings online this month.

The target is an enzyme called PPT1, which controls both the mechanistic target of rapamycin (mTOR), a major regulator of growth in cells, as well as a process called , a built-in resistance mechanism which allows cells to survive when under attack by breaking down unneeded parts and recycling them to stay alive. Numerous drugs that target mTOR are approved by for by the U.S. Food and Drug Administration, but targeting mTOR with these currently available inhibitors turns on autophagy, thus making the tumor resistant.

"What we learned in this study is that mTOR and autophagy aren't opposed to each other as previously thought. They're actually complementary, because autophagy provides the nutrients that allow mTOR to direct growth, while mTOR shuts off autophagy when the nutrients aren't needed," said co-senior author Ravi K. Amaravadi, MD, an associate professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania and a member of Penn's Abramson Cancer Center.

That yin and yang relationship takes place in a part of the cell called the lysosome. Previously, it has taken two drugs to stop both processes, but by focusing on drugs that hone in on the lysosome more efficiently, researchers have found one that can block both. "We know that autophagy is an important mechanism for cancer resistance, but there are very few ways to block it. This is the first targeted approach to inhibiting the lysosome in order to block autophagy," Amaravadi said.

The drug that makes it work is called DQ661, and it specifically targets the PPT1 enzyme that controls both mTOR and autophagy. This study suggests drugs that PPT1 in this way could one day improve outcomes for cancer patients. DQ661 is a dimeric form of the antimalarial drug quinacrine - meaning it has two molecules of quinacrine bound together with a special linker.

"It turns out that both what is linking them and how they are linked are crucial to why this works," said the study's co-senior author Jeffrey D. Winkler, the Merriam Professor of Chemistry in the School of Arts and Sciences at the University of Pennsylvania. "In this study, we were able to tailor the chemistry so that the drug specifically targets PPT1 in the lysosome."

The lead authors of the study were Vito W. Rebecca, PhD, a postdoctoral researcher in Amaravadi's lab, Michael C. Nicastri, a graduate student in Winkler's lab, and Noel McLaughlin, PhD, who was a in Winkler's lab at the time of the research. Winkler says the ability to work across multiple disciplines is what led to the discovery.

"As (Amaravadi) and his team tried to solve the autophagy problem, they came to us for help in developing a better form of quinacrine, which is what we have in DQ661," Winkler said.

While the approach has clear clinical benefits, researchers still need to develop these compounds into drugs that are suitable for human patients, which will be the focus of their efforts moving forward.

Explore further: Link established between a molecular driver of melanoma and novel therapeutic agent

More information: Vito W. Rebecca et al, A unified approach to targeting the lysosome's degradative and growth signaling roles., Cancer Discovery (2017). DOI: 10.1158/2159-8290.CD-17-0741

Related Stories

Link established between a molecular driver of melanoma and novel therapeutic agent

September 7, 2017
Results of a study by The Wistar Institute have described a correlation between a key melanoma signaling pathway and a novel class of drugs being tested in the clinic as adjuvant therapy for advanced melanoma, providing useful ...

Block its recycling system, and cancer kicks the can: study

May 8, 2012
All cells have the ability to recycle unwanted or damaged proteins and reuse the building blocks as food. But cancer cells have ramped up the system, called autophagy, and rely on it to escape damage in the face of chemotherapy ...

Blocking autophagy with malaria drug may help overcome resistance to melanoma BRAF drugs

February 24, 2014
Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression.

Study reveals PGK1 enzyme as therapeutic target for deadliest brain cancer

February 23, 2017
Discovery of a dual role played by the enzyme phosphoglycerate kinase 1 (PGK1) may indicate a new therapeutic target for glioblastoma, an often fatal form of brain cancer, according to researchers at The University of Texas ...

New drug squashes cancer's last-ditch efforts to survive

June 25, 2015
As a tumor grows, its cancerous cells ramp up an energy-harvesting process to support its hasty development. This process, called autophagy, is normally used by a cell to recycle damaged organelles and proteins, but is also ...

Study suggests that autophagy inhibitors could improve efficacy of chemotherapies

October 24, 2016
Chemotherapies treat cancer by killing tumor cells, but certain types of chemotherapy can also drive an immune system response to target and destroy the remaining tumor cells.

Recommended for you

Study tracks evolutionary transition to destructive cancer

February 23, 2018
Evolution describes how all living forms cope with challenges in their environment, as they struggle to persevere against formidable odds. Mutation and selective pressure—cornerstones of Darwin's theory—are the means ...

Researchers use a molecular Trojan horse to deliver chemotherapeutic drug to cancer cells

February 23, 2018
A research team at the University of California, Riverside has discovered a way for chemotherapy drug paclitaxel to target migrating, or circulating, cancer cells, which are responsible for the development of tumor metastases.

Lab-grown 'mini tumours' could personalise cancer treatment

February 23, 2018
Testing cancer drugs on miniature replicas of a patient's tumour could help doctors tailor treatment, according to new research.

An under-the-radar immune cell shows potential in fight against cancer

February 23, 2018
One of the rarest of immune cells, unknown to scientists a decade ago, might prove to be a potent weapon in stopping cancer from spreading in the body, according to new research from the University of British Columbia.

Putting black skin cancer to sleep—for good

February 22, 2018
An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes ...

Cancer risk associated with key epigenetic changes occurring through normal aging process

February 22, 2018
Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.