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Co-clinical mouse/human trials aim to speed up drug approvals

The many breakthroughs in understanding the pathways involved in leukemia have delivered a double-edged sword: hundreds of new drugs await testing but an insufficient patient pool exists to conduct clinical testing in a timely way. The research community has historically used mouse models as a precursor to human clinical testing to identify the best compounds to invest in human studies.

Pier Paolo Pandolfi, MD, PhD (BIDMC), Director, Cancer and Genetics Program, BIDMC Cancer Center, and Leukemia Program Co-Leader, has developed a promising new twist on the use of mouse models in cancer research in the effort to accelerate the process by which genetic determinants that would predict sensitivity or resistance to these new experimental therapeutics are identified. Using genetically engineered mice that express human faulty genes mimicking the complexity of human cancers, his strategy is to optimize new cancer therapies – either singly or combinatorially – in real time. In essence, his mouse models offer a mirror image of the human patient experience.

“We call it a co-clinical trial approach,” says Pandolfi. “The proposed plan of action is for a drug to reach the human clinic and be tested in mouse models at the same time.” Investigators may then conduct trials simultaneously and integrate the data accrued.

Testing pas de deux

The strategy is a tandem approach. “By doing it in synchronicity with the human effort the information we get in the mouse can be validated in humans and vice versa,” says Pandolfi. Since the mice trials move much more quickly they are intended to be predictive of response in people.

The mouse modeling component has significantly evolved in the last 10-15 years.  “Literally, for each and every cancer we can now express in the mouse in a cell-tissue-specific manner virtually anything we want from mutant genes and germline SNP variations, to translocation products to non-coding RNA to recreate the complexity of human cancer with great accuracy,” explains Pandolfi. He says that engineering mice in this manner to include the relevant information found in human cancer, recreating this in a “faithful” model of disease, allows investigators to assess which determinants and mutations have an impact on therapy. “You study biology to know which genetic element is the driver, and use these mouse models as little patients to study the response to drugs,” says Pandolfi.  His goal is to accelerate the process and support the pharmaceutical companies to identify the patient population that will be responsive hence allowing them to get rapid FDA approval for drugs likely to be successful in patient groups with a specific genetic makeup.

Co-clinical approach applied in acute promyelocytic leukemia

This strategy is currently being used to optimize treatment modalities in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia. There are six genetic APL variants with differential responses to therapy. Mouse models were generated for each type of APL and used to tell clinicians which drug or combination would be effective. When the human clinical trial was initiated, investigators were able to confirm what they had already seen in the mouse models.

Role beyond cancer

Pandolfi recently received a $4.2 million grant from the National Cancer Institute to pursue the co-clinical mouse model approach in two pilot studies in prostate and lung cancers.  The program, entitled “The Co-clinical Project: Informing Clinical Trials Using Preclinical Mouse Models,” includes investigators across DF/HCC, including Lewis Cantley, PhD (BIDMC), Kwok-Kin Wong, MD, PhD (DFCI), Jeffrey Engelman, MD, PhD (MGH), Glenn Bubley, MD (BIDMC), John Frangioni, MD, PhD (BIDMC), and Ralph Weissleder, MD, PhD (MGH).

“In the larger scheme, the idea is to employ this model not only for prostate, lung, and leukemia cancers but for all cancers and beyond that for other diseases,” says Pandolfi. “This platform can be exported for diabetes, metabolic disorders, or autoimmunity, for example, because you can recreate in the mouse the genetic causes not only of disease but susceptibility.”

—Alice McCarthy