Methods for treating cancer with a WEE1 inhibitor
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. 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) calculating an evidence score based on an additive point value for each identified TP53 gene mutation; and
3) predicting the patient as responsive to treatment with the WEE1 inhibitor when the evidence score is equal to or greater than 2.0;
wherein the evidence score for a TP53 gene mutation of step (2) is calculated by (a) assigning to each type of TP53 gene mutation a point value related to a likelihood that the mutation results in a loss of function of p53 protein; and (b) adding together the TP53 gene mutation point values to afford the evidence score.
2. The method of claim 1 , wherein the process of predicting the patient as responsive to respond to treatment with the WEE1 inhibitor further comprises calculating a point value for each type of TP53 gene mutation patient.
3. The method of claim 1 , wherein the at least one TP53 gene mutation is 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, M237I, 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, S2151, 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, at least one basepair insertion or deletion in the TP53 gene that causes a frameshift in encoding a p53 protein resulting in loss of function, and a combination thereof in the cancer cells.
4. The method of claim 3 , wherein the patient has at least one TP53 gene mutation resulting in an amino acid change selected from the group consisting of C238F, R248W, R273L, a stop codon at the codon encoding E298 in the p53 protein, and a deletion of a basepair in the codon encoding V157 in the p53 protein.
5. The method of claim 1 , wherein the at least one TP53 gene mutation results in a loss of function of p53 protein.
6. The method of claim 1 , wherein the WEE1 inhibitor is
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the WEE1 inhibitor is
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , 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.
9. The method of claim 8 , wherein the cancer is ovarian cancer.
10. The method of claim 8 , wherein the cancer is lung cancer.
11. The method of claim 1 , wherein the additional anti-cancer agent is selected from the group consisting of: 5-FU, carboplatin, paclitaxel, doxorubicin, etoposide, gemcitabine, irinotecan, mitomycin, temozolomide, topotecan, and a combination thereof.
12. The method of claim 11 , wherein the additional anti-cancer agent is carboplatin.
13. The method of claim 11 , wherein the additional anti-cancer agents are carboplatin and paclitaxel.
14. The method of claim 1 , wherein the one or more additional anti-cancer agents are administered subsequent to administering the WEE1 inhibitor to the patient.
15. The method of claim 14 , wherein the method does not comprise administering the one or more additional anti-cancer agents prior to administering the WEE1 inhibitor.
16. The method of claim 1 , wherein the point value assigned for each type of TP53 gene mutation is selected from:
(a) a stop codon mutation (truncated protein) prior to codon 306 has a point value of 3;
(b) a splice site mutation between codons 97 and 375 has a point value of 3;
(c) a frameshift mutation has a point value of 3;
(d) a dominant negative mutation has a point value of 2;
(e) a P53 signature score p-value <0.05 vs. wild type (WT) has a point value of 1;
(f) a transactivation loss-of-function mutation has a point value of 1;
(g) mutations reported over ten times in at nucleotide level in International Agency for Research on Cancer (IARC) TP53 database has a point value of 0.5; and,
(h) mutations reported over ten times in somatic tissue at amino acid level in IARC TP53 database has a point value of 0.5.