Moffitt Researchers Discover New Targets for Approved Cancer Drug

New study shows ALK inhibitor ceritinib may have the ability to be used for more than ALK-rearranged non-small cell lung cancer

Developing new drugs to treat cancer can be a painstaking process taking over a decade from start to Food and Drug Administration approval. Scientists are trying to develop innovative strategies to identify and test new drugs quicker and more efficiently. A team of researchers at Moffitt Cancer Center used cellular drug screening, functional proteomics and computer-based modeling to determine whether drugs with well-known targets may be repurposed for use against other biological targets. They found that an FDA approved drug for non-small cell lung cancer called ceritinib has anti-cancer activity against previously unknown targets. Their results were published today in the journal, Nature Chemical Biology.

For the past 20 years, there has been an emphasis on targeted cancer therapy – targeting a specific driver of cancer development to minimize side effects typically seen with chemotherapy. This personalized approach has been successful in certain types of cancer that are primarily driven by a single DNA alteration, such as found in chronic myeloid leukemia. However, the majority of cancers are not caused by a single mutation; rather, cancer is more commonly caused by a large network of mutations and alterations. Some researchers, including those from Moffitt, are beginning to rethink the targeted approach to cancer therapy. They believe that developing drugs that act on multiple targets, called a polypharmacology approach, may more effectively treat those cancers that have a network of alterations.

In order to identify drugs that act on multiple targets, Moffitt researchers screened 240 drugs that are either FDA approved or in clinical development. They noticed that the drug ceritinib acts differently than other drugs in its class. Ceritinib targets a protein called ALK, and is approved to treat patients with ALK-rearranged metastatic non-small cell lung cancer. Their research found that ceritinib also inhibits the growth of lung cancer cells that do not have genetic alterations in the ALK gene.

After an extensive set of experiments to learn how ceritinib worked in cells without ALK rearrangements, they discovered the drug inhibits several other previously unknown targets, and that these signals converge onto a protein known to be responsible for causing drug resistance to paclitaxel. Importantly, the researchers showed that ceritinib combined with paclitaxel was more effective than either agent alone at reducing cell viability.

These findings suggest that ceritinib together with paclitaxel may be effective against other cancers that do not have ALK rearrangements, and that this drug combination may be used to target a network of changes in cancer.

“The results also demonstrate the benefits of using a combined screening, proteomics and computer-based modeling approach to identify drugs that act on multiple targets and to determine how they function,” said study lead author Uwe Rix, Ph.D., assistant member of the Drug Discovery Program at Moffitt. “In the future, this strategy may facilitate further drug repurposing efforts and lead to an increase in new therapy options for patients with difficult-to-treat diseases.”

Georgetown Clinical Trial of Nilotinib in Alzheimer’s Disease Begins

 A clinical trial to examine the effect of nilotinib on clinical outcomes and biomarkers in people with mild to moderate Alzheimer’s disease has opened at Georgetown University Medical Center (GUMC).

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of the cancer drug(Tasigna®). GUMC is conducting the study with its clinical partner, MedStar Georgetown University Hospital.

The rationale for using nilotinib is based on laboratory and clinical research conducted by the Georgetown Translational Neurotherapeutics Program (TNP). Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in the brain. Both are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear the Tau, Abeta and other toxic proteins.

“In a 2015 proof of concept study at Georgetown, patients with Parkinson’s disease or dementia with Lewy bodies were treated with nilotinib. As my colleagues reported, those who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers—the same biomarkers seen in Alzheimer’s,” explains Scott Turner, MD, PhD, medical co-director of the TNP, who will serve as principal investigator for the study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study give an even stronger rationale.”

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Charbel Moussa, MB, PhD, scientific and clinical research director for the Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, it appears nilotinib turns on autophagy for about four to eight hours—long enough to clean out the cells without causing cell death. Toxic proteins that build up again then appear to be cleared when the drug is given again the next day.”

Moussa initially conducted the preclinical research that led to the discovery of nilotinib for the potential treatment of neurodegenerative diseases.

Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases.

The Alzheimer’s Drug Discovery Foundation is supporting this clinical trial through a $2.1 million grant to Turner. The study has also received private philanthropic support.

Turner conducts additional clinical research supported by funding to Georgetown University from Lilly, Biogen, Merck, Acadia, and Toyama as well as the National Institutes of Health and Department of Defense.

To learn more about this clinical trial, please click here. To learn about other Alzheimer’s clinical studies, please visit the Georgetown Memory Disorders Program website.

Researchers Find Fungus-Fighting Compound in Drug Discovery Center Library

Researchers with the Virginia Tech Center for Drug Discovery have identified a compound that blocks the growth of a fungus that causes deadly lung infections and allergic reactions in people with compromised immune systems.

The research team targeted the switch that allows the fungus Aspergillus fumigatus to survive in iron-deficient conditions like the human body. Specifically, they targeted an enzyme known as SidA, which is essential for the synthesis of molecules called siderophores that are made during infection to steal iron from human proteins.

Furthermore, by performing high-throughput screening in the center’s Drug Discovery Screening Laboratory, they found a compound called Celastrol that blocks the growth of iron-producing organelles in the fungus.

The results were published in the journal ACS Chemical Biology.

“This project shows what an asset the screening lab is to the community,” said Pablo Sobrado, a professor of biochemistry in the College of Agriculture and Life Sciences and director of the screening laboratory. “Without the robots and chemical libraries available at the screening lab, this work would not have been possible. We are very fortunate at Virginia Tech to have this facility.”

Aspergillus fumigatus is common and is typically found in soil and decaying organic matter. Most people are exposed to it daily with little consequence, but it can cause lung damage in people with compromised immune systems, such as organ transplant recipients and people with AIDS or leukemia. The mortality rate of this population, when exposed to the fungus, is more than 50 percent, according to the authors.

“Growing antibiotic resistance is demanding the development of target-directed therapies,” said Julia S. Martin del Campo, a postdoctoral research scientist in Sobrado’s lab. “This approach requires the discovery of enzyme inhibitors that block essential pathogen pathways. The discovery of Celastrol as a SidA inhibitor represents the first building block in the development of drugs against A. fumigatus and related pathogens.”

The Lauder and Newhouse Families Announce New Initiative to Find Treatments for Frontotemporal Degeneration

As of 2016, we still don’t have a single approved drug to cure or even slow the progression of diseases caused by damage to the brain’s neurons. The Alzheimer’s Drug Discovery Foundation (ADDF) and The Association for Frontotemporal Degeneration (AFTD) are determined to change that. Today, they announce a $10 million investment to develop effective treatments for frontotemporal degeneration (FTD), a complex form of dementia that affects more than 50,000 people in the United States.

The Lauder Foundation, Leonard A. Lauder, President, and Ronald S. Lauder have jointly committed $5 million, which will be combined with $5 million from the Samuel I. Newhouse Foundation to create The Treat FTD Fund. The fund, a joint program of AFTD and the ADDF, will accelerate clinical trials for FTD over the next decade. And it has the potential to advance treatments for other neurodegenerative diseases, such as Alzheimer’s, ALS and Parkinson’s.

Leonard A. Lauder, ADDF Board Co-Chairman, said: “My brother and co-chairman, Ronald S. Lauder, and I founded the ADDF to find treatments for Alzheimer’s and other causes of dementia. Partnerships have always been an important part of that mission because they allow us to combine resources and to develop effective drugs faster.”

Donald Newhouse, President of Advance Publications, Inc., added: “My wife, Susan, suffered from primary progressive aphasia, a form of FTD. My brother, Si, suffers from the same dementia. Si’s wife, Victoria, and I and our families are committed to research to find treatments and a cure for FTD and Alzheimer’s. This partnership between the ADDF and AFTD is a significant step forward in carrying out our commitment.”

The partners are optimistic that this initiative will encourage more funders to invest in drug research for FTD and other devastating neurodegenerative diseases. Walter J. Koroshetz, MD, Director of the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, remarked: “The challenge of developing effective treatments for persons with FTD calls for an ‘all hands on deck’ effort. Collaborations like this one will bring great scientists to work on FTD, and set a tone of hope for what NIH and the private sector can achieve together.”

The ADDF and AFTD plan to support new drugs in clinical trials, as well as “repurposed” drugs. Repurposing, in which drugs approved for one disease are used for others, is a growing area of research because it pares down the enormous costs and time of traditional drug development. The Treat FTD Fund will build on recent successes of both foundations in early-stage drug discovery and biomarker development that make clinical trials possible and increase their odds of success. A “Request for Proposals,” expected to be announced this summer, will be available at www.alzdiscovery.org and www.theaftd.org.