Oncology

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A Novel Hypoxia Activated EGFR Inhibitor Kills Two Birds with One Stone Bringing Hope for Resistant Lung Cancer

by Federica Parisi PhD, April 28, 2015 at 08:00 AM | Tags

Misregulation of the epidermal growth factor receptor (EGFR) gene is a common theme in cancer biology and consistent efforts have been made to identify the underlying mutations driving tumorigenesis. However some forms of cancer retain one normal copy of EGFR, suggesting the existence of a more general physiological trigger for EGFR aberrant activation. A recent study, presented during this year meeting of the American association for cancer research (AACR), in Philadelphia, showed promising results for a new compound called TH-4000 that is activated upon shortage of oxygen and stably inhibits EGFR activity reducing tumor growth in lung cancer models.

Hypoxia is a common condition for the majority of human tumors in which the cancerous lesion itself and the surrounding regions are deprived of an adequate oxygen supply. This phenomenon occurs as a consequence of the fast pace at which cancer cells grow and it has been proven to play an important role in tumor progression. Lung cancer (i.e. NSCLC) is a hypoxic type of tumor and has been linked with aberrant activation of EGFR. Standard of care for EGFR overexpressing tumors consists in treatment with drugs like erlotinib or gifitinib that belong to the tyrosine kinase inhibitors (TKIs) family, which work by inhibiting the receptor’s molecular function.

Clinical studies on NSCLC indicate that the forms of this tumor that are associated with reduced response to conventional TKIs, short progression-free survival, and poor overall survival are heterozygous for EGFR mutation, meaning that they retain one normal (wild type) copy of the EGFR gene, while the second copy is mutated. We now understand that tumor hypoxia is responsible for the poor response to chemotherapy of these NSCLC patients because oxygen shortage within the tumor environment is able to over activate the wild type copy of EGFR, driving drug resistance.

A team of researchers from the Auckland Cancer Society Research Centre, partnering with Threshold Pharmaceuticals has been working on a new anticancer compound for over a decade and presented their work last week during AACR. Their big efforts were directed towards the design of a drug, called TH-4000 that could be activated during hypoxia to irreversibly inhibit EGFR, targeting both aspects of drug resistance in NSCLC at the same time.

The team headed by Adam Patterson and Jeff Smaill, was able to show both in vitro and in vivo, that TH-4000 produced 100% tumor regression in animal models with wild type EGFR that are resistant to erlotinib as well as in EGFR mutated tumor models that respond to standard targeted therapy. Data from a previous Phase I clinical trial were also presented at AACR, showing the efficacy of the drug in inducing solid tumors regression. In September 2014, Threshold acquired exclusive worldwide rights for the clinical development of TH-4000 that is now ready to advance to human Phase II clinical trial to treat patients with tumors that are not candidate for conventional TKIs therapy.

Crown Bioscience attended AACR. Our team welcomed researchers and collaborators at our booth and presented scientific results at our posters, which covered different aspects of drug discovery research ranging from our latest results in immune targeted combination therapy to the application of image-guided irradiation to preclinical in vivo models.

Crown Bioscience is happy to see that increasingly more efforts are dedicated to the development of new treatments for NSCLC patients in which conventional TKI therapy has failed. Crown bioscience has a long-standing track record of research in lung cancer. Our large, commercially available HuPrime® and PDXact™ collections of >1,600 genomically characterized patient-derived xenografts (PDX) includes several lung cancer models that can be used to run HuTrials, preclinical Phase II-like, human surrogate trials to evaluate your oncology agents. Combining this with our HuMark translation platform, which spans a range of experiments and analyses from tissue collection to human surrogate trial data analysis, allows you to predict biomarkers of response to your agent, and help to validate antitumor effects against predicted human targets.

Contact us at busdev@crownbio.com to talk to our experts on how we can further your translational oncology needs through our patient-derived xenograft models and translational oncology resources today.


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