KIF5B-RET fusion molecules and uses thereof

Inventors

Downing, Sean R. • Hawryluk, Matthew J. • Lipson, Doron • Parker, Alexander N. • Stephens, Philip James

Assignees

Foundation Medicine Inc

Abstract

Novel RET fusion molecules and uses are disclosed.

Core Innovation

The disclosed subject matter relates to KIF5B-RET fusions in patient samples and to methods that use determination of the presence of a KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide. The disclosure includes KIF5B-RET nucleic acids and polypeptides, defined by in-frame exon junction configurations and domain composition, including a RET tyrosine kinase domain and KIF5B kinesin motor and coiled-coil domains.

Detection concepts include nucleic-acid-based and protein or biomarker detection approaches, with fusion status determined from mRNA, cDNA, expression evidence, and protein or biomarker evidence. The document further relates to identifying KIF5B-RET fusions and their breakpoints using massively parallel sequencing and other assays in FFPE tumors, and to detection assays and detection reagents including PCR, NGS, FISH with break-apart probes, immunodetection, probes, primers, baits, and antibodies that distinguish wild-type RET and/or KIF5B from fusion-containing forms.

Therapeutic concepts are described as using determination of KIF5B-RET fusion status followed by administration of an effective amount of a kinase inhibitor or a RET-specific inhibitor to a subject having thyroid cancer. The document also includes nucleic-acid targeting approaches for KIF5B-RET fusion expression inhibition and RET inhibition concepts, and screening or evaluation uses to identify or evaluate agents that modulate fusion activity, binding, phosphorylation, or downstream signaling.

The document further describes clinical trial cohort repurposing based on post-hoc KIF5B-RET screening, including screening of NSCLCs using IHC and RT-PCR sequencing, as well as fusion recurrence screening and drug-susceptibility model concepts for evaluating susceptibility to RET inhibitors such as sunitinib and vandetanib.

Claims Coverage

The independent claim coverage centers on biomarker-directed treatment for thyroid cancer and a domain-defined KIF5B-RET fusion polypeptide. Two inventive features are consistently present: determining the presence of a KIF5B-RET fusion polypeptide or encoding nucleic acid, and administering a kinase inhibitor or a RET-specific inhibitor.

Across the independent claim, treatment is directed by determinization of KIF5B-RET fusion presence, using polypeptide or encoding nucleic acid, and is administered as kinase inhibitor or RET-specific inhibitor therapy for thyroid cancer, where the KIF5B-RET fusion polypeptide is characterized by a RET tyrosine kinase domain, a KIF5B kinesin motor domain, and a KIF5B coiled-coil domain of SEQ ID NO:2.

Stated Advantages

Documented Applications