Methods for treating cancer with a wee1 inhibitor

Abstract

The present invention relates generally to the use of gene mutations, whose presence or absence are useful for predicting a patient's response to treatment with an anti-proliferative agent, in particular a WEE1 inhibitor. The presence or absence of a mutation to the TP53 gene, can be used to predict response to treatment with a WEE1 inhibitor in a patient presenting with a cancerous condition.

1 - 17 . (canceled) 
     
     
         18 . A method of treating cancer in a patient having one or more TP53 gene mutations, the method comprising administering to the patient a therapeutically effective amount of a WEE1 inhibitor and optionally one or more additional anti-cancer agents, wherein the patient is predicted to be responsive to treatment with the WEE1 inhibitor, the process of prediction comprising:
 1) identifying all TP53 gene mutations in a patient tumor tissue sample comprising cancer cells;   2) predicting the patient to be responsive to treatment with the WEE1 inhibitor when the patient has:
 a. a stop codon mutation prior to codon 306, 
 b. a splice site mutation between codons 97 and 375, 
 c. a frameshift mutation, 
 d. a dominant negative mutation, 
 e. a P53 signature score p-value<0.05 vs. WT and a transactivation loss of function mutation, 
 f. a P53 signature score p-value<0.05 vs. WT and two or more of:
 i. a mutation reported greater than 10 times in somatic tissue at nucleotide level or 
 ii. a mutation reported greater than 10 times in somatic tissue at amino acid level, 
 
 g. a transactivation loss of function mutation and two or more of:
 i. a mutation reported greater than 10 times in somatic tissue at nucleotide level or 
 ii. a mutation reported greater than 10 times in somatic tissue at amino acid level, or 
 
 h. four or more of:
 i. a mutation reported greater than 10 times in somatic tissue at nucleotide level or 
 ii. a mutation reported greater than 10 times in somatic tissue at amino acid level. 
 
   
     
     
         19 . The method of  claim 18 , wherein the TP53 gene mutations are selected from the group consisting of E2, K120, V143M, A159D, C176F, R196P, C229, C242S, R249S, C275G, R282G, E3, C124, V143A, A161D, C176Y, V197G, Y234H, C242, P250L, C275Y, R282W, Q5, Y126, Q144, Y163N, C176S, E198, Y234C, C242W, I255F, C275F, R282P, S6, S127P, L145Q, Y163H, C176, G199, Y234, G244S, L257Q, C275S, R282Q, Ell, S127T, L145P, Y163D, C176W, G199E, Y236D, G244C, L257P, C275, R283H, Q16, S127F, W146, Y163C, P177S, L201, Y236H, G244R, E258, C275W, R283P, E17, S127Y, D148, Y163S, P177H, E204, Y236N, G244D, E258K, A276P, E285, S20, S127C, P151T, Y163, P177R, Y205D, Y236C, G244V, D259Y, C277Y, E285K, W23, K132, P151S, K164, H179N, Y205S, Y236S, G244A, D259V, C277F, E285V, K24, K132Q, P151A, K164E, H179Y, Y205C, Y236, G245S, N263, C277, E286, E28, K132E, P151R, Q165, H179R, Y205, M2371, G245R, L265P, P278T, E286K, L35, K132R, P151H, S166, H179L, L206, C238R, G245C, G266, P278S, E286Q, Q38, K132M, P152S, Q167, H179Q, R209, C238Y, G245D, G266R, P278A, E286G, L43, K132T, P152L, H168Y, H179, R213, C238F, G245V, G266E, P278H, E286V, E51, K132N, G154V, H168R, E180, R213Q, C238, G245A, G266V, P278L, E286A, Q52, M133K, T155P, H168P, C182, R213L, N239D, M246V, R267W, P278R, E286D, W53, C135R, T155N, H168L, S183, H214R, N239S, M246L, R267P, G279E, E287, E56, C135S, R156P, E171, S183, S215I, N239, M246R, F270C, R280, N288D, E62, C135G, V157F, V173M, Q192, V216M, S240G, N247I, E271, R280G, K291, R65, C135Y, V157L, V173L, H193Y, V216L, S241T, N247T, V272M, R280T, K292, E68, C135F, V157D, V173G, H193D, V216E, S241A, R248W, R273C, R280K, E294, W91, C135S, V157G, V173E, H193N, V216G, S241P, R248G, R273S, R2801, E298, S94, C135, V157A, R175G, H193L, Y220N, S241F, R248Q, R273G, R280S, K305, Q100, C135W, R158G, R175C, H193P, Y220H, S241C, R248L, R273H, D281N, R306, K101, Q136, R158S, R175H, H193R, Y220D, S241Y, R248P, R273L, D281Y, R337C, Y103, A138P, R158P, R175L, L194F, Y220C, C242S, R249W, R273P, D281H, Q104, A138G, R158H, R175P, L194R, Y220S, C242R, R249G, V274F, D281G, Y107, K139, R158L, C176R, I195F, Y220, C242G, R249M, V274A, D281V, R110L, C141Y, A159P, C176S, I195T, E221, C242Y, R249K, C275R, D281A, L114, C141, A159V, C176G, R196, E224, C242F, R249T, C275S, D281E, and a combination thereof in the cancer cells. 
     
     
         20 . The method of  claim 18 , wherein the WEE1 inhibitor is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . The method of  claim 18 , wherein the WEE1 inhibitor is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method of  claim 18 , wherein the cancer is selected from the group consisting of ovarian cancer, melanoma, lung cancer, colorectal cancer, colon cancer, rectum cancer, prostate cancer, and breast cancer. 
     
     
         23 . The method of  claim 22 , wherein the cancer is ovarian cancer. 
     
     
         24 . The method of  claim 22 , wherein the cancer is lung cancer. 
     
     
         25 . The method of  claim 18 , wherein the one or more additional anti-cancer agents are selected from the group consisting of: 5-FU, carboplatin, paclitaxel, doxorubicin, etoposide, gemcitabine, irinotecan, mitomycin, temozolomide, topotecan, and a combination thereof. 
     
     
         26 . The method of  claim 25 , wherein the one or more additional anti-cancer agents is carboplatin. 
     
     
         27 . The method of  claim 25 , wherein the one or more additional anti-cancer agents are carboplatin and paclitaxel. 
     
     
         28 . The method of  claim 18 , wherein the one or more additional anti-cancer agents are administered subsequent to administering the WEE1 inhibitor to the patient. 
     
     
         29 . The method of  claim 18 , wherein the method does not comprise administering the one or more additional anti-cancer agents prior to administering the WEE1 inhibitor.