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.”

Drug targeting technique could aid therapies for immune diseases

A new technique that targets drugs to specific cells could lead to improved therapies for diseases caused by an overactive immune response.

The approach could help people affected by conditions such as arthritis and inflammatory bowel diseases, where the body’s own immune system mistakenly attacks healthy tissues.

Researchers focused on a group of immune cells called macrophages – some of which help the body heal after injury, while others can promote harmful inflammation.

The team at the University of Edinburgh sought to devise a new therapy to remove harmful macrophages while leaving healing cells unaffected

They coupled a drug compound to a carrier molecule that only becomes active in acidic conditions, such as those found inside harmful macrophages.

A fluorescent tag attached to the molecules enabled the team to track the cells affected by the drug.

Lab tests on human macrophages showed the treatment preferentially affected inflammatory macrophages and did not affect healing cells.

Studies with zebrafish, which share features of their immune system with people, found the treatment helped to improve the recovery of tissues after injury.

The team hopes their approach could lead to more effective therapies, with fewer side effects, for the treatment of immune-related diseases.

Their research was published in the journal ACS Central Science.

Dr Marc Vendrell, of the Medical Research Council Centre for Inflammation Research at the University of Edinburgh, who led the study, said: “This is an important step forward in the design of more precise drugs with fewer side effects. In future studies, we want to exploit this technology to improve the treatment of diseases in which macrophages and immune cells are important.”

Inhibitor drug improves overall survival in older radioiodine resistant thyroid cancer

The drug lenvatinib can significantly improve overall survival rates in a group of thyroid cancer patients whose disease is resistant to standard radioiodine treatment, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The study, published today in the Journal of Clinical Oncology, is the first to show lenvatinib has a definitive impact on overall survival (OS). Researchers found OS improves in patients older than 65 years of age and that the drug is well-tolerated.

“Due to limitations of study design, it has been hard to prove that multikinase inhibitors improve overall survival, although we have suspected it,” said the study’s lead author Marcia Brose, MD, PhD, an associate professor of Otorhinolaryngology and a member of Penn’s Abramson Cancer Center. “These findings put that doubt to rest for the group of patients over 65 treated with lenvatinib.”

Most cases of differentiated thyroid cancer (DTC) are treated with radioiodine therapy. Since the thyroid absorbs nearly all of the iodine in the human body, radioactive iodine given to a patient will concentrate in thyroid cancer cells, killing them with little effect on the rest of the body. The treatment can be curative, but about 15 percent of DTC patients have cancers that are resistant to the therapy.

Levatinib is one of two first-line therapies approved by the U.S. Food and Drug Administration for patients who are resistant to radioiodine treatment. The drug is a multi- kinase inhibitor (MKI) — meaning it targets the specific enzymes that are required for growth in DTC.

“It was approved based on previous trials that showed it had a benefit for progression-free survival, but until now, nobody has shown it also has a benefit for overall survival,” Brose said.

Brose and her team participated in the SELECT trial to study the effects of levatinib on DTC, and Brose directed the further analysis published in this report which specifically looked at OS and safety of lenvatinib in younger and older patients. Patients were divided into two groups: Those 65 or younger, and those older than 65. The median age of the younger group was 56. For the older group, it was 71. Each group contained patients on the drug and patients receiving a placebo.

Researchers found significant differences in overall survival between those on the drug and those on the placebo in the older age group. Among the older cohort, those on the placebo had an OS of 18.4 months. For patients receiving the drug, OS was not reached, but confidence intervals show the expected survival would exceed 22 months. In the younger cohort, overall survival was not reached for either group.

“There’s a belief that these drugs should be withheld from older patients due to concerns about toxicity and other medical concerns, but our results show just the opposite,” Brose said. “Not only do older patients benefit from these drugs, but they generally tolerate them well.”

Brose says the results of this study can have an immediate impact in clinical care, and several other studies are ongoing to find new uses for lenvatinib in other types of thyroid cancer.

Drug Developed at University of Minnesota Increases Survival in Dogs with Cancer

A breakthrough trial at the University of Minnesota testing a new UMN-developed drug resulted in improved survival rates for dogs diagnosed with a cancer called hemangiosarcoma (HSA). The results were published today in the journal Molecular Cancer Therapeutics.

“This is likely the most significant advance in the treatment of canine HSA in the last three decades,” said study co-author Jaime Modiano, V.M.D., Ph.D. professor in the University of Minnesota College of Veterinary Medicine and member of the Masonic Cancer Center, University of Minnesota.

Canine HSA is a common, aggressive, incurable sarcoma. It is remarkably similar to angiosarcoma, which affects humans. Both cancers typically spread before diagnosis and the survival time for affected patients is extremely short, even with aggressive treatment. Only 50% of humans diagnosed with angiosarcoma live longer than 16 months and the prognosis for dogs with HSA is similarly dire: less than 50% will survive 4-6 months and only about 10% will be alive one-year after their diagnosis.

The study tested a drug called eBAT, invented by study senior author Daniel Vallera, Ph.D., professor at the University of Minnesota Medical School and Masonic Cancer Center.

“eBAT was created to specifically target tumors while causing minimal damage to the immune system. HSA is a vascular cancer, meaning it forms from blood vessels. eBAT was selected for this trial because it can simultaneously target the tumor and its vascular system,” said Vallera.

Traditional cancer treatments have side effects that can be very hard on patients. “In this trial we aimed for a sweet spot by identifying a dose of eBAT that was effective to treat the cancer, but caused no appreciable harm to the patient. Essentially we’re treating the cancer in a safer and more effective way, improving quality of life and providing a better chance at survival,” lead study author Antonella Borgatti, D.V.M., M.S., associate professor with the University of Minnesota College of Veterinary Medicine said.

eBAT was tested on 23 dogs of various breeds, both large and small, with HSA of the spleen. Dogs received three treatments of eBAT after surgery to remove the tumor and before conventional chemotherapy. The drug treatment improved the 6-month survival rate to approximately 70%. Furthermore, five of the 23 dogs that received eBAT treatment lived more than 450 days.

The positive results for canine patients, the similarities between this cancer and angiosarcoma in humans, and the fact that many other tumor types can be targeted by eBAT, make a strong case for translating this drug into clinical trials for human cancer patients. The researchers want these results to bring hope to those touched by this disease.

“This drug was invented here at the University of Minnesota, developed here, manufactured here, tested here and showed positive results here. We would also like this drug to achieve positive outcomes for humans here,” Modiano said.

“The ultimate goal for all of us is to create a world in which we no longer fear cancer,” Modiano said.

This project is an example of the remarkable progress that is being made through collaborations among the multiple colleges and schools within the University of Minnesota’s Academic Health Center.

Funding was provided by many sources, including various foundations and individuals along with the National Institutes of Health, showing the broad interest in identifying cures for these devastating cancers.

Eli Lilly, Biogen, and Neurotrope Fight to Find Viable Treatment for Alzheimer’s Disease

Repeated attempts to treat or even slow the relentless progression of Alzheimer’s disease by targeting just one red flag in patient’s brains have continued to lead to disappointing outcomes.

Last Sunday “Sixty Minutes” episode aired on Columbian extended families that inherited a genetic defect that causes early onset Alzheimer’s, by the time they reach 45 years old.

Watching the episode brings to light another case in which a young lady with a different genetic mutation caused her to be afflicted with Alzheimer’s, at the age of 30 years old.

That young lady lost the ability to swallow, causing her to be hooked up to a feeding tube.  She also lost the ability to move her limbs and recognize people.  Dr. Alkon, currently President and Chief Scientific Officer of Neurotrope, (NTRP) was allowed under an FDA compassionate use program to treat the young lady.  She was treated with a drug called bryostatin, which is not a statin, it activates PKC epsilon.  Within a short time she was able to recognize people, extend her arm to reach out to her husband and begin to swallow. This allowed her to be removed from the feeding tube so that she could drink from a straw and eventually regain the ability to speak some words.

The activation of PKC epsilon activates the main amyloid degrading enzymes, ECE, neprilysin, and IDE while activating Alpha Secretase.  Alpha Secretase has been a target for treating Alzheimer’s.  The problem has been finding a safe one.  Eli Lilly’s(LLY) and Biogen’s (BIIB) drugs are monoclonal antibodies that inhibit amyloid beta.  But Lilly’s drug, solanezumab, just failed a major Phase III trial, showing it was no better at slowing down cognitive decline than placebo. Merck (MRK) has a BACE inhibitor that also inhibits amyloid beta.  Neurotrope’s bryostatin, in addition to degrading amyloid, also normalizes GSK3 beta.  That mechanism prevents the hyperphosphorylation of tau.  So you don’t have to be a tauist or a baptist, bryostatin hits both targets.

Incredibly, bryostatin also activates growth factors in the brain, such as BDNF, NGF and IGF-1.  This mechanism causes synaptogenesis.  That allows the brain to restore damaged synapses and grow new synapses. The hope is that the damage caused by Alzheimer’s disease may actually be reversed through this mechanism.

Dr. Alkon didn’t start out by trying to find a drug to fight Alzheimer’s.  He was leading a department at the NIH trying to find out how to increase memory and he came upon PKC epsilon.  PKC epsilon was the conductor in the center of the orchestra, arranging the different mechanisms to create the masterpiece of memory.

Take that, Eli Lilly and Biogen.  You guys have to give your drugs extremely early in the disease, to have any hope of your drugs working, because you need to treat patients before any damage to the synapses has occurred.  So far all those drugs have failed, and the excuse is always that they haven’t been given early enough in the disease process.  If bryostatin can reverse the disease in moderate to severe patients, the drug would be given in all stages.  Perhaps even for prevention in the early onset mutations or APOE4 cases.  Yes, Dr. Alkon even has performed preclinical studies showing that bryostatin can counteract the negative genetic mechanism of the APOE4 gene.

The data that the company will be releasing in five months, April 2017, from their 148 patient Phase II placebo controlled trial.  Multi modal efficacy of bryostatin targeting PKC epsilon, versus everyone else’s drugs, that are just trying to hit one target.  It isn’t even a fair fight. Neurotrope’s bryostatin, if approved, is a blockbuster for one of the largest unmet medical needs in the world today.