Two exciting early phase clinical trials are underway at Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, that leverage novel classes of drugs and exploit how proteins can be targeted and/or removed to stop uncontrolled cell division that occurs in sarcomas and solid tumors.
For BRAF B600 mutated cancers (Lung, Colorectal, Melanoma, Anaplastic Thyroid Cancers)
Clinical trial CFT1946 is open for adult patients ages 18+ who have been diagnosed with a BRAF V600 mutation and who have failed standard-of-care therapy for locally advanced or metastatic disease. The study is evaluating the use of a specific PROteolysis TArgeting Chimera (PROTAC). PROTACs are molecules that can target a protein and prompt its destruction and ultimate removal from cells.
“PROTACs take advantage of the body’s natural mechanism to remove unnecessary or unwanted proteins,” notes Washington University oncologist Brian Van Tine, MD, PhD, director of Siteman’s Developmental Therapeutics and Sarcoma Programs. “They are engineered to bind to a target protein, drag it into the body’s own ‘trashcan,’ and then destroy it.”
A mutation in the BRAF protein causes cells to become stuck in a continuous “on” position so they keep dividing, which can lead to tumor development. Patients with the BRAF mutation can be treated with inhibitors that slow down and turn “off” cell division, but those drugs cannot remove the abnormal protein from the body. PROTACs, on the other hand, destroy and eliminate the target protein through the proteasome. They are part of a growing field called targeted protein degradation (TPD) therapy.
“The actual removal of a targeted protein offers a key advantage,” says Van Tine. “Standard-of-care therapies for the treatment of sarcomas often result in drug resistance, which then requires increasingly higher doses or changes in drugs to target the protein involved. PROTACs take out the targeted protein completely and may, then, eliminate the complication of drug resistance.”
Worldwide, several PROTACs are moving through clinical trials. In the past two years, Washington University researchers at Siteman Cancer Center have completed a phase 1 trial of a different PROTAC that Van Tine said showed proof of principle for the therapeutic approach. Promising results here and elsewhere are rapidly escalating the number of clinical trials involving PROTACs.
Antibody Drug Conjugate (ADC) Clinical Trial for Axl-Expressed Cancers, Including Soft Tissue Sarcomas, Pancreatic Cancer and Non-Small Cell Lung Cancer
Another early phase clinical trial for adults ages 18+ is part of a growing class of therapeutics called antibody drug conjugates (ADCs). ADCs are specialized molecules equipped with a payload of cancer-killing drugs. They are designed to seek and then bind to a targeted protein on the outside of a cancer cell, then insert their anti-cancer drug directly into the cell.
“As long as you can hook onto your target, you can kill it with an ADC,” says Van Tine. “These are advanced, precision medicine therapeutics that are prompting the dawning of a new age in the fight against cancer.”
This latest ADC clinical trial targets Axl, a tyrosine kinase receptor that is overexpressed in many solid and hematologic tumors. Tyrosine kinases are a group of proteins that are found on the surface of cells and regulate cell signaling, growth and differentiation. Abnormal genes within these proteins can lead to unregulated cell growth and cancer. By targeting Axl, clinical researchers hope to stop the growth of tumor cells in Axl-expressed cancers in many soft tissue sarcomas and non-small cell lung cancers as well as pancreatic cancer.
The excitement over ADCs is based on their impact on standard-of-care therapy for a variety of cancers. For example, in a clinical trial for HER2-positive metastatic breast cancer, the use of an ADC, ENHERTU, resulted in a 72% reduction in risk of tumor progression or death when compared with standard-of-care therapy. ADCs also have demonstrated better tolerability with fewer side effects than chemotherapy drugs. The FDA approved the first ADC, Mylotarg, in 2000 for acute myeloid leukemia. Since then, more than a dozen have been approved worldwide, with hundreds more in clinical trials. Their use has broadened from treating late-stage blood cancers to treating earlier cancer stages. Six ADCs currently are approved for use in solid tumors.
“There are many ADCs coming to Siteman Cancer Center that are in clinical trials or are in line for FDA approvals,” says Dr. Van Tine. “In the era of precision medicine, it behooves patients and physicians to check what’s in the pipeline. Advancements in the use of ADCs are rapidly coming to the forefront, and we will almost double our portfolio of cancer-fighting therapeutics in the near term.”
For information about these or other open clinical trials at Siteman Cancer Center, visit siteman.wustl.edu, or call 314-747-3046.