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Basic biology is the wellspring from which flow many modern clinical therapies used to treat diseases rare and common, ranging from immune deficiencies, blood malignancies, and epilepsy to hypertension, diabetes, and many types of cancer. Indeed, most life-altering medical treatments are rooted in curiosity-driven science that delves into the molecular inner workings of cells, tissues, and organs.
However, with some notable exceptions, the process is fraught, protracted, and can lead to numerous — and often costly — dead ends. It could take several decades for a basic discovery to become a new medicine.
The Harvard Medical School’s Blavatnik Therapeutics Challenge Awards (BTCAs) program, now in its fourth year, is designed to optimize this process and help push promising early discoveries toward clinic, said Ifat Rubin-Bejerano, senior director of translational research at HMS.
“Through these generous grants, we aim to forge a stronger bond between HMS and its affiliated hospitals, cultivating promising projects, offering expertise in drug discovery and development, and helping build and execute their research plans and envision their path to the clinic,” said Rubin-Bejerano.
The 2023 BTCA grants have been awarded to early-stage discoveries that could eventually result in new therapies for osteoarthritis, non-small cell lung cancer, anemia, and multiple myeloma. Each award recipient will receive $1 million over two years to advance the work.
“This year’s winning projects embody the spirit of our collective quest as scientists to ensure that fundamental insights made in the lab are propelled through translation and, eventually, taken to the clinic,” said HMS Dean George Q. Daley. “The essence of our work toward improving health and well-being for all begins with bridging the gap between discoveries made with molecules and cells and actual frontline therapies used in patients.”
Here are the funded projects for 2023:
Off-the-shelf tissue to repair damaged cartilage
Principal investigator April Craft, HMS assistant professor of orthopedic surgery at Boston Children’s Hospital
- The challenge: Damage to the cartilage lining our joints, known as articular cartilage, can lead to osteoarthritis (OA), a condition that affects an estimated 528 million people around the globe, according to the World Health Organization. If left untreated, OA can lead to progressive deterioration of all tissues within the joint, causing chronic pain and disability. Joint cartilage cannot repair itself after injury, and there is no treatment that adequately restores cartilage structure and function. Thus, an exceedingly large — and growing — number of patients must deal with debilitating pain for decades.
A possible solution: Craft and her colleagues have developed novel methods to generate new articular cartilage tissue from human pluripotent stem cells. Preliminary studies using this approach resulted in significantly improved outcomes in the knees of rats.
The BTCA will help Craft’s team move forward to evaluate the long-term efficacy of this novel, low-risk, cost-effective, single-step, interventional tissue-based treatment to repair damaged cartilage in a large animal model. Restoring the joint cartilage is expected to reduce pain and prevent or delay the onset of OA, thus increasing the quality of life for many people.
A new targeted therapy for non-small cell lung cancer
Principal investigators Michael Eck, HMS professor of biological chemistry and molecular pharmacology at Dana-Farber Cancer Institute, and David Scott, director of the Medicinal Chemistry Core at Dana-Farber
- The challenge: Like many cancers, non-small cell lung cancer — a subtype that makes up the majority of lung cancers — can arise from a single genetic mutation with more cancer-fueling mutations developing in response to treatments. A protein called epidermal growth factor receptor (EGFR) is often mutated in non-small cell lung cancer. Although several FDA-approved drugs directly target EGFR mutations, additional mutations typically develop over time that are resistant to these treatments, leaving patients without viable treatment options.
A possible solution: Eck, Scott, and their colleagues are developing a new compound, EAI-432, to target a specific type of EGFR mutation called L858R. This experimental drug is active against tumors driven by L858R. Because the drug targets a different site of EGFR, it retains its potency even in the presence of mutations that cause resistance to EGFR-targeted drugs.
Eck’s team is working to complete a series of studies that would set the stage for clinical trials with EAI-432. The BTCA will help fund these and other studies to test the efficacy of this drug in combination with an FDA-approved EGFR inhibitor. The ultimate goal, the researchers say, is to use this precision-targeted therapy to improve outcomes for patients with lung cancer fueled by this subset of EGFR mutations.
A novel way to treat anemia of chronic disease
Principal investigator Eric Gale, HMS assistant professor of radiology at Massachusetts General Hospital
The challenge: Anemias associated with chronic kidney disease and other chronic conditions are often complicated by inflammation that disrupts the transport of iron throughout the body. In this condition, known as iron restriction, or functional iron deficiency, inflammation prevents iron from traveling to the bone marrow, where it is needed to make red blood cells. This occurs when a protein called ferroportin — responsible for ferrying iron out of the cells – gets stuck inside cells.
As a result, iron cannot reach another important carrier, a protein called transferrin, which usually takes up the iron released by ferroportin and delivers it into the bone marrow. Current treatment approaches—intravenous iron and iron-containing nutritional supplements — do not work well because the iron cannot pass through the blocked ferroportin.
A possible solution: Gale and colleagues have come up with an approach that overcomes the critical defect in iron transportation. They have designed a novel drug that bypasses the blocked ferroportin and replenishes the iron-carrying protein transferrin directly, rapidly, and with high precision.
Preliminary experiments show that the drug restores hemoglobin levels in mice with a rare form of anemia called iron-refractory iron-deficiency anemia, and that the drug is tolerated well. The BTCA will fund studies to establish the therapeutic effectiveness and safety of the new drug, compared with the standard-of-care treatments for anemia related to chronic kidney disease. It will further fund early drug development necessary for translation to use in humans.
Boosting the activity of CAR T cells against multiple myeloma
Principal investigator Mohammad Rashidian, HMS assistant professor of radiology at Dana-Farber
- The challenge: Chimeric antigen receptor (CAR) T cell therapy has redefined treatment of several blood cancers, such as multiple myeloma. The approach involves reprogramming a patient’s own T cells, which are a type of immune cell, to target and eliminate cancer. However, the effectiveness of this therapy is hampered by T cell exhaustion, in which the modified T cells lose their potency over time, allowing cancer to return aggressively.
A possible solution: Rashidian and his colleagues have introduced an approach known as CAR-enhancer, designed to specifically target CAR T cells and boost their activity and persistence. This strategy aims to counteract CAR T cell exhaustion, guiding the CAR T cells to develop durable and functional memory cells. The funding provided by BTCA will support the research team in advancing the development of CAR-enhancer for CAR T cells designed to recognize a protein often overexpressed in multiple myeloma cells.
The CAR-enhancer treatment is expected to reduce the likelihood of relapse in patients.
Dual-targeted “OR-logic” gated CAR T cell therapy to cure multiple myeloma
Principal investigator Eric Smith, Dana-Farber
- The challenge: Multiple myeloma is largely an incurable disease, in which patients’ response to treatments diminishes over time. Chimeric antigen receptor (CAR) T cell therapy, a treatment in which patients’ T cells are modified to recognize proteins on cancer cells and launch an attack on the cancer, can help extend survival. However, this therapy rarely provides a cure and can lead to relapse. Thus far, CAR T cell therapy for multiple myeloma has targeted a single cancer-cell protein, B-cell maturation antigen (BCMA).
A possible solution: Borrowing from other approaches to treating cancer and infectious diseases through multiple pathways to prevent relapse, Smith’s team is developing a multi-targeted CAR T cell therapy to prevent escape from BCMA-targeted treatment. The researchers developed small fully human antibodies — nanobodies — that target multiple tumor proteins on cells. Experiments so far show that chimeric antigen receptors (CARs) incorporating these nanobodies effectively eliminate cancer cells, including multiple myeloma cells missing a potential target protein.
The BTCA will provide funding to further develop these lead candidate CARs and identify refined candidate for an effective CAR T therapy, an important step toward testing this approach in clinical trials. Furthermore, Smith’s team will evaluate the safety of the approach by testing its tendency to cause a rare but dangerous side effect known as cytokine release syndrome, marked by a severe immune reaction.
The awards are part of the Therapeutics Initiative at HMS, an effort to harness the School’s long-standing strength in fundamental discoveries of the basic mechanisms of biology and disease, design new treatments, and advance them to the clinic. BTCA investigators will work closely with Mark Namchuk, executive director of therapeutics translation at HMS, and his team at the HMS Therapeutics Translator, which aims to advance early-stage drug discovery through expert stewardship of internal therapeutics development platforms.
The initiative and the awards were made possible by a transformational $200 million gift from the Blavatnik Family Foundation, the largest gift in HMS history.
