The Testa lab investigates the role of hereditary and somatic mutations in malignant mesothelioma, a cancer of the cells lining the chest and abdominal cavities, primarily caused by exposure to asbestos.  The group discovered frequent mutations of the CDKN2A locus, a region of DNA that encodes the tumor suppressors p16INK4A and p14ARF, and NF2 in human mesothelioma.  In 2011, he and his collaborators also discovered germline mutations of the BAP1 tumor suppressor gene in families with a high incidence of mesothelioma, the first study demonstrating that inherited mutations can influence a person’s risk of mesothelioma.  Besides mesothelioma, some of the BAP1 mutation carriers developed ocular melanoma or other cancers, and this cancer susceptibility is now recognized as the BAP1 tumor predisposition syndrome.  Much of the current work in the lab is focused understanding the mechanisms involved in BAP1-related tumor susceptibility.  Using a genetically-engineered mouse (GEM) model they developed, the Testa lab provided the first in vivo evidence that inherited (germline) mutation of Bap1 predisposes to the development of asbestos-induced mesothelioma. This and other Bap1 mouse models are currently being used to assess susceptibility to spontaneous lung formation and  gene–environment interactions.  The group is also using novel GEM models to unravel the role of asbestos-induced inflammation in the genesis of malignant mesothelioma.

Mechanistic work by the Testa lab previously linked NF2 inactivation to oncogenic PAK and FAK signaling, implicating NF2 inactivation in mesothelioma cell spreading, invasiveness and proliferation, thereby establishing a framework for elucidating tumorigenic mechanisms and novel therapeutic targets in this disease.   Other in vivo studies demonstrated that alterations of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive mesotheliomas characterized by enhanced tumor dissemination and the involvement of a cancer stem cell (CSC) population.  Mesothelioma is very difficult to treat and almost always recurs after therapy.  Based on his work linking NF2 loss to FAK activation, he partnered with investigators in the pharmaceutical industry to test a novel drug that blocks FAK activity.  Their findings suggested that FAK inhibitor treatment might be especially beneficial in patients with NF2-deficient tumors.  Moreover, the drug proved to be particularly effective at killing CSCs, which can give rise to recurrent tumors.  These preclinical studies provided the rationale for a clinical trial in mesothelioma patients using a FAK inhibitor as a single agent after first-line chemotherapy. Other planned preclinical studies involve the use of a FAK inhibitor with inhibitors of other pathways that are commonly activated in human mesotheliomas.

Testa has a longstanding interest in the oncogenic role of AKT, beginning with his chromosomal mapping of the AKT1 proto-oncogene in 1988.  The Testa lab cloned and characterized the related AKT2 gene and provided the first evidence for recurrent alterations of the AKT pathway in human cancers.  The group is currently investigating the role of an AKT interactor, the adapter APPL1/2, in embryonic development and oncogenesis.  The lab is also characterizing how other genes, such as the proto-oncogene  Myc or the homeobox gene Dlx5 cooperate with Akt2 to promote oncogenesis.

The Testa lab is highly interactive and currently collaborates with, and shares funded grants with, both the Chernoff and Balachandran labs at FCCC, on studies designed to target various kinases aberrantly activated in mesothelioma.  Additionally, collaborative grants with Frank Rauscher (Wistar) on BAP1 and Rebecca Simmons (UPenn) on mouse models of asbestos carcinogenicity are ongoing.