Researching Radiosensitizers, a New Class of Drugs That Would Make Tumors More Vulnerable to Radiation Therapy

Two out of three cancer patients are treated with radiation, but the therapy often fails to wipe out the tumor or slow its growth. Southern Research is working to develop a new class of drugs that will help the radiation deliver a more powerful punch to the disease.

Dr. Bo Xu, M.D., Ph.D., Distinguished Fellow and Chair of Southern Research’s Oncology Department, said a radiosensitizer would greatly benefit cancer patients by improving the success rate of radiation by reducing resistance to the treatment.

“Our project focuses on making those tumor cells more vulnerable to radiation by targeting a critical survival mechanism that allows them to recover from the effects of radiation,” Xu said.

It’s a challenging project, in the works for almost a decade. It got started when Southern Research scientists began looking at fundamental biology concepts to identify a pathway that could play a role in the ability of cancer cells to survive radiation.

They discovered that disrupting the tumor’s self-protection mechanism – in this case, an interaction between two specific proteins – makes the cancer more sensitive to radiation treatment, Xu said.

“The whole idea is to use this strategy to find a new drug that can be used by patients who receive radiation. This drug wouldn’t have toxicity because if it got into the cell it wouldn’t mess up the major functions of the protein network,” he said.

“It would only work when radiation is delivered, and that radiation would be more effective. It’s like a catalyst.”

Using funding from the Alabama Drug Discovery Alliance (ADDA), a partnership with the University of Alabama at Birmingham, Southern Research scientists recently scanned thousands of compounds to identify potential drug candidates. The focus now is to validate the results of those scans and to identify lead compounds for more testing.

“Our hope is that in three years, we can identify a novel class of radiosensitizers that can help the approximately two-thirds of cancer patients who will eventually receive radiotherapy,” Xu said.

While some forms of cancer, such as lymphoma, are sensitive to radiation therapy, many others are not. Solid tumors with a low supply of oxygen, called hypoxic tumors, are tough to treat with radiation. So are cancer cells with a high DNA-repair capability.

To develop a radiosensitizer, Xu is taking aim at a protein that binds to DNA and recognizes the damage being done by radiation. The protein then joins forces with an enzyme to initiate a molecular repair job.

“If that recruitment is successful, then the DNA damage will be repaired, and the cancer cell will survive,” Xu said. “What we’re trying to do is to block this protein from finding the other one, so that the repair process will be diminished or affected. That way, the tumor cells will die.”

To prevent the DNA repair job from getting started, Xu is investigating a small peptide mimic, a small sequence of amino acids that is similar to a human protein but just a fraction of its size. These strands get to the site to block the interaction of the two natural, full-size proteins.

“This interference makes the cancer cell more vulnerable to radiation treatment,” he said.

Radiosensitizers are in demand, but they have proved difficult to develop. While the concept has been around for half a century, very few radiosensitizers have actually become available, according to Xu.

“While there are compounds that work synergistically with radiation, there are few drugs that were developed as a pure radiosensitizer,” he said.

In addition to the ADDA, the National Institutes of Health and the Department of Defense prostate cancer program have provided Southern Research with funding for this research over the years.

Q BioMed Gears up for Production of Cancer Pain Palliation Drug with Commercial Launch Expected in Q2 2017

Q BioMed Inc, a NYC-based biomedical acceleration and development company has begun process validation for the manufacturing of a non-narcotic analgesic treatment for pain associated with metastatic bone cancer. The drug, a generic Strontium Chloride 89 injection, provides long-lasting relief for patients suffering from debilitating bone pain due to metastatic cancer, typically caused by advanced-stage breast, prostate or lung cancer. It has been proven to provide a long-term effect — resulting in cancer pain relief and enhanced quality of life.

There are approximately 350,000 cases of patients living with bone metastases in the U.S. alone. In addition, 380,000 new diagnoses of patients with breast, prostate and lung cancer occur every year and approximately 1 in 3 of those will develop bone metastases.

The delivery of an affordable, non-narcotic pain therapy is a much needed and underutilized option for this patient population and coincides well with the recently passed 21st Century Cures Act combating opiate overuse and abuse. The Act, provides $1 billion in funding over the next two years for opioid addiction prevention and treatment programs to develop, promote and use non-narcotic alternative therapies.

The commercialization of the drug allows Q BioMed to deliver an effective and much needed alternative to hundreds of thousands of suffering patients. The company said in a statement that they are very pleased to offer this U.S. Food and Drug Administration approved therapy to patients in the very near term and are currently negotiating with US-based contract manufacturing organization (CMO) agreements and expect to have those completed along with the commercial launch in Q2 2017.

The company recently closed on its 2nd tranche of the $4,000,000 funding announced on November 30th 2016. The company received $1,000,000 on the 2nd closing bringing the total received to date to $2.5MM and expect to receive the remaining $1.5MM upon effectiveness of their recently filed registration statement on Form S-1.

Q BioMed is focused on licensing and acquiring biomedical assets across the healthcare spectrum. The company provides these target assets the strategic resources, developmental support, and expansion capital they need to ensure they meet their developmental potential, enabling them to provide products to patients in need.

Antibody Drug Conjugates May Help Personalize Radiotherapy For Patients With Cancer

Many types of cancer become drug resistant, making them difficult to treat. Researchers with University of California San Diego School of Medicine and Moores Cancer Center have identified a strategy to selectively sensitize certain cancer cells to radiation therapy that may improve tumor control and reduce treatment-related side effects.

In a paper published October 4 in Nature Communications, researchers report that in mouse models tumors testing positive for a protein called human epidermal growth factor receptor 2 (HER2) were sensitized to a combination of radiation therapy and an antibody drug conjugate (ADC) called ado-trastuzumab emtansine (T-DM1). ADC is a new technology that chemically links an antibody to a targeted cell receptor to deliver a drug to specific cells — in this case a very potent chemotherapy to HER2 positive tumors — while sparing normal tissue.

“A biomarker-driven, tumor-targeted radiosensitization approach to treating cancer is a potentially significant advancement from current chemotherapy and radiation therapy,” said Sunil J. Advani, MD, associate professor in the Department of Radiation Medicine and Applied Sciences and the paper’s senior author. “Non-targeted, highly toxic chemotherapies continue to remain the most effective treatments for patients treated concurrently with chemotherapy and radiation, but these treatments have significant toxicity and we need alternatives that are molecularly guided based on mutations found in specific patients. Our approach is to use antibodies to restrict delivery of powerful drugs to cancer cells that sensitize tumors to radiation therapy.”

The study shows promise in HER2 cancers, which occur in a percentage of lung, esophageal, gastric and bladder cancers.

T-DM1 is already approved for use in metastatic HER2 positive breast cancer treatment. Researchers repurposed the existing drug to sensitize cancer cells to radiation therapy among patients who simultaneously receive chemotherapy and radiation therapy at the beginning of the treatment process, instead of waiting until the cancer spreads or becomes resistant to treatment.

Intensifying a dose of non-targeted chemotherapies increases normal tissue toxicities, often precluding further radiation therapy or chemotherapy escalation. Using targeted ADC with radiation therapy would reduce toxicity, reduce the risk of tumor resistance and attacks both known tumors as well as cancer cells that may have metastasized, while sparing normal tissue.

“Our hope is that the results can transition to clinical studies quickly to help patients with advanced cancers that are difficult to treat with standard therapies,” said Stephen R. Adams, PhD, project scientist in the Department of Pharmacology and first author on the paper.

FDA Greenlights Orphan Drug Status for Radioimmuneconjugate for Treating Refractory and Relapsed Acute Myeloid Leukemia in Elderly Patients

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation for Iomab-B, a radioimmunotherapeutic that conditions relapsed and refractory Acute Myeloid Leukemia (AML) patients for a Hematopoietic Stem Cell Transplant (HSCT), commonly referred to as a Bone Marrow Transplant (BMT). Iomab-B will soon begin a 150 patient, pivotal Phase 3 multicenter trial in relapsed and refractory AML patients over the age of 55.

Iomab-B is a radioimmunoconjugate consisting of BC8, a novel murine monoclonal antibody, and iodine-131 radioisotope. BC8 has been developed by the Fred Hutchinson Cancer Research Center to target CD45, a pan-leukocytic antigen widely expressed on white blood cells. This antigen makes BC8 potentially useful in targeting white blood cells in preparation for hematopoietic stem cell transplantation in a number of blood cancer indications, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin’s disease (HD), Non-Hodgkin lymphomas (NHL) and multiple myeloma (MM). When labeled with radioactive isotopes, BC8 carries radioactivity directly to the site of cancerous growth and bone marrow while avoiding effects of radiation on most healthy tissues.

Sandesh Seth, Executive Chairman of Actinium Pharmaceuticals, the company developing Iomab-B said in a prepared statement, “We are pleased to have been granted orphan drug status by the FDA for Iomab-B, particularly ahead of its pivotal Phase 3 clinical trial. There has not been a new drug approved for relapsed and refractory AML patients over the age of 55 in decades and with Iomab-B being the only therapy of its kind, we are pleased to have achieved this important milestone. Orphan drug status for Iomab-B follows Actimab-A, which was granted the designation in November 2014. Orphan drug status provides Actinium with several development and financial incentives, including seven years of market exclusivity in the United States, if Iomab-B receives marketing approval and exemption from prescription drug user fees.”

The FDA, through its Office of Orphan Products Development (OOPD), grants orphan status to drugs and biologic products that are intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. Orphan drug designation provides a drug developer with certain benefits and incentives, including a period of marketing exclusivity if regulatory approval is ultimately received for the designated indication; potential tax credits on U.S. clinical trials; eligibility for orphan drug grants; and waiver of certain administrative fees.

Pharma Company Funds Saint Louis University Researcher’s Quest to Treat His Daughter’s Disease

A team of Saint Louis University scientists led by Fran Sverdrup, Ph.D., developing a treatment for his daughter’s muscular dystrophy, has new funding for their research, thanks in part to a California-based biopharmaceutical company named Ultragenyx, which is focused on the development of novel products for rare and ultra-rare diseases.

SLU’s Center for World Health and Medicine, has entered into a three-year collaboration to advance a potential treatment identified by Sverdrup for Facioscapulohumeral Muscular Dystrophy (FSHD), a disease that causes muscle degeneration in 15,000 or more people in the U.S.

Sverdrup’s daughter was diagnosed with FSHD in 2011, one year after he joined the Center for World Health and Medicine, an initiative launched by SLU to develop new therapies for rare and neglected diseases.  He immediately began a relentless search for treatments, and learned that no therapies were available. However, as a scientist at a drug discovery center, he had access to the tools and skills needed to make a difference.

“When my daughter was diagnosed with FSHD, I realized I had the opportunity to jump in and do something about it. The very mission of the center allowed me to start a new research project, a project aimed at finding a therapy for my own daughter,” said Sverdrup, a research fellow at the center.

“I was in the right place, with a talented group of researchers, very passionate individuals, who wanted to take up that cause with me.”

In 2012, Sverdrup discovered a class of compounds that appears to turn off the toxic gene that is inappropriately expressed in FSHD muscle cells, which could correct the defect.

Four years later, SLU and Ultragenyx inked an agreement that has the potential of taking Sverdrup’s discoveries to the next level – the development of a treatment for FSHD.

“My daughter is a very smart, very beautiful girl with a rewarding life in front of her. I want to do everything I can to make certain that happens,” Sverdrup said.

Emil Kakkis, M.D., Ph.D., CEO and president of Ultragenyx Pharmaceuticals, said his San Francisco Bay Area company is motivated to help those who have FSHD.

“SLU has a great start scientifically and we’re excited to begin a robust collaboration to bring forward what we hope will be the first treatment for this debilitating and progressive disease,” Kakkis said.

Ultragenyx will fund the process of turning SLU’s initial discoveries into a drug that could demonstrate proof-of-concept. If successful, Ultragenyx will then conduct human clinical trials to test the safety and effectiveness of the new therapy.

“By combining our center’s specialized drug development capabilities with the rare disease expertise of Ultragenyx, I’m optimistic our collaboration will increase the chances of delivering an effective therapy to patients with FSHD,” said Pete Ruminski, executive director for SLU’s Center for World Health and Medicine.

Because a therapy for FSHD would be considered an orphan drug, a designation of medications developed for rare diseases, it could be eligible for expedited reviews and potentially fast-tracked through the clinical trial process by the Food and Drug Administration, which approves all new medications, he added.

Sverdrup is eager to take the next steps on his project.

“I’m thrilled that we have a committed partner who is intent on driving this forward as quickly as possible, to get this into the clinic,” Sverdrup said.

“Our goal is to develop the first therapy for all patients with this disease, including my daughter. This is an important step in a long, often difficult process, certainly a great milestone in our efforts to bring a therapy forward.”