Novel kif5b-ret fusion molecules and uses thereof

Abstract

Novel RET fusion molecules and uses are disclosed.

1 . A method of reducing an activity of a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, comprising:
 optionally, acquiring knowledge of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide; and   contacting the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, or a KIF5B-RET-expressing cell, with an agent that inhibits an activity or expression of KIF5B-RET.   
     
     
         2 .- 5 . (canceled) 
     
     
         6 . A method of treating a subject having cancer, comprising:
 acquiring knowledge of the presence of a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide in said subject; and   administering to the subject an effective amount of an anti-cancer agent, thereby treating cancer in the subject.   
     
     
         7 . The method of  claim 6 , wherein said anti-cancer agent is a kinase inhibitor. 
     
     
         8 . The method of  claim 7 , wherein the kinase inhibitor:
 (i) is administered responsive to the determination of presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide in a tumor sample from said subject;   (ii) inhibits the expression of the nucleic acid encoding the KIF5B-RET fusion polypeptide;   (iii) is selected from an antisense molecule, a ribozyme, an RNAi molecule, or a triple helix molecule, each of which hybridizes to a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, or a transcription regulatory region that blocks or reduces mRNA expression of the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide; or   (iv) is administered in combination with a second therapeutic agent or a different therapeutic modality.   
     
     
         9 . The method of  claim 6 , wherein:
 (i) said administration is administered responsive to acquiring knowledge or information of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide in said subject;   (ii) said administration is administered responsive to acquiring knowledge or information of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide in said subject from another party;   (iii) said administration is administered responsive to an identification of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide in the subject, wherein said identification arises from collaboration with another party;   (iv) the method comprises receiving a communication of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide in the subject; or   (v) the method comprises determining the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide by sequencing.   
     
     
         10 .- 13 . (canceled) 
     
     
         14 . The method of  claim 6 , wherein:
 (i) said cancer is chosen from pancreatic cancer, melanoma, colorectal cancer, esophageal-gastric cancer, thyroid cancer, or adenocarcinoma; or   (ii) said cancer is lung cancer, and wherein said lung cancer is chosen from: small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma (SCC), adenocarcinoma of the lung, bronchogenic carcinoma, or a combination thereof.   
     
     
         15 .- 18 . (canceled) 
     
     
         19 . The method of  claim 6 , wherein the anti-cancer agent is:
 (i) a multi-kinase inhibitor;   (ii) a RET-specific inhibitor;   (iii) sorafenib (NEXAVAR®);   (iv) sunitinib (SUTENT®, SU11248);   (v) vandetanib (CAPRELSA®, ZD6474); or   (vi) NVP-AST487.   
     
     
         20 .- 35 . (canceled) 
     
     
         36 . A method of determining the presence of a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide comprising:
 directly acquiring knowledge that a KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is present in a sample from a subject.   
     
     
         37 . The method of  claim 36 , wherein said sample:
 (i) comprises fluid, a cell, a circulating tumor cell, tissue, a tumor tissue, or a tumor biopsy; or   (ii) is a nucleic acid sample or a protein sample.   
     
     
         38 .- 41 . (canceled) 
     
     
         42 . The method of  claim 36 , wherein the subject has a cancer, wherein the cancer:
 (i) is chosen from a colorectal cancer, an esophageal-gastric cancer, a thyroid cancer, an adenocarcinoma or a melanoma; or   (ii) is a lung cancer, and wherein the lung cancer is chosen from: a NSCLC, a SCLC, a SCC, or a combination thereof.   
     
     
         43 .- 44 . (canceled) 
     
     
         45 . The method of  claim 36 , wherein:
 (i) a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is detected, wherein the detection comprises sequencing by a method chosen from one or more of: a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time PCR, sequencing, screening analysis, FISH, spectral karyotyping, MFISH, comparative genomic hybridization, in situ hybridization, SSP, HPLC or mass-spectrometric genotyping;   (ii) the KIF5B-RET fusion polypeptide is detected; or   (iii) the level or activity of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is evaluated.   
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 36 , comprising acquiring a sequence for a position in a nucleic acid molecule by sequencing at least one nucleotide of the nucleic acid molecule, wherein the sequence acquired is compared to a reference sequence, or a wild type reference sequence,
 thereby determining that a nucleic acid molecule encoding a KIF5B-RET fusion polypeptide is present.   
     
     
         48 .- 49 . (canceled) 
     
     
         50 . The method of  claim 36 , comprising: contacting a protein sample with a reagent which specifically binds to a KIF5B-RET fusion polypeptide; and detecting the formation of a complex of the KIF5B-RET fusion polypeptide and the reagent, wherein:
 the reagent is labeled with a detectable group to facilitate detection of the bound and unbound reagent; or   the reagent is an antibody molecule.   
     
     
         51 .- 53 . (canceled) 
     
     
         54 . The method of  claim 36 , wherein the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is detected:
 (i) prior to initiating, during, or after, a treatment in the subject;   (ii) at the time of diagnosing the subject with a cancer; or   (iii) at a pre-determined interval, wherein the pre-determined interval comprises a first point in time and at least at a subsequent point in time.   
     
     
         55 .- 56 . (canceled) 
     
     
         57 . The method of  claim 36 , comprising, responsive to a determination of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, one or more of:
 (1) stratifying a population comprising the subject, wherein stratifying comprises assigning the subject to a class, wherein the class comprises a candidate classified to receive a treatment that comprises a kinase inhibitor;   (2) identifying or selecting the subject as likely or unlikely to respond to a treatment;   (3) selecting a treatment option for the subject; or   (4) prognosticating the time course of the disease in the subject.   
     
     
         58 . The method of  claim 57 , wherein the treatment option comprises administering a kinase inhibitor, and optionally wherein the kinase inhibitor is chosen from: sorafenib (NEXAVAR®); sunitinib (SUTENT®, SU11248); vandetanib (ZACTIMA®, ZD6474); or NVP-AST487. 
     
     
         59 .- 62 . (canceled) 
     
     
         63 . The method of  claim 36 , wherein responsive to the direct acquisition of knowledge of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide:
 (i) the subject is classified as a candidate to receive a treatment that comprises a kinase inhibitor;   (ii) the subject is assigned to a class, wherein the class comprises a candidate classified to receive a treatment that comprises a kinase inhibitor, if a KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is identified in a sample from the subject; or   (iii) the subject is identified as likely to respond to a treatment that comprises a kinase inhibitor.   
     
     
         64 .- 66 . (canceled) 
     
     
         67 . A method of evaluating a subject, comprising:
 identifying, selecting, or obtaining information or knowledge that the patient has participated in a clinical trial or has been treated for cancer;   acquiring genotype information that identifies a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide as being in the subject,   wherein the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide identifies the subject as having an increased risk for, or having, a cancer associated with the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide; and   treating the subject with a kinase inhibitor.   
     
     
         68 . The method of  claim 67 , further comprising providing a report to a party. 
     
     
         69 . The method of  claim 68 , wherein:
 (i) the party is the patient, a caregiver, a physician, an oncologist, a hospital, clinic, third-party payor, insurance company or government office;   (ii) said report is in electronic, web-based or paper form; or   (iii) the report identifies the presence or absence of an alteration, and optionally includes an identifier for the subject.   
     
     
         70 .- 71 . (canceled) 
     
     
         72 . The method of  claim 68 , wherein said report comprises:
 information on the role of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, or wildtype KIF5B or RET sequence, in disease;   information on prognosis, resistance, or potential or suggested therapeutic options;   information on the likely effectiveness of a therapeutic option, the acceptability of a therapeutic option, or the advisability of applying a therapeutic option to the subject; or   information, or a recommendation on, the administration of a drug to the subject.   
     
     
         73 . (canceled) 
     
     
         74 . An isolated or purified nucleic acid molecule that encodes a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide or a breakpoint comprising fragment thereof. 
     
     
         75 . (canceled) 
     
     
         76 . An isolated or purified vector comprising the nucleic acid molecule of  claim 74 . 
     
     
         77 . A host cell comprising a vector of  claim 76 . 
     
     
         78 . A nucleic acid molecule that specifically reduces or inhibits the expression of the nucleic acid molecule of  claim 74 . 
     
     
         79 . (canceled) 
     
     
         80 . A nucleic acid molecule suitable as a probe, primer, bait or library member that can specifically identify, capture, detect, or isolate the nucleic acid molecule of  claim 74 . 
     
     
         81 .- 87 . (canceled)