Method for treating cancer
Provided herein are methods related to methods of predicting sensitivity to NER-targeting agents for the treatment of cancer. In one aspect, provided herein is a method for treating cancer in a subject) of at least 0.70 and the anti-cancer treatment comprises an alkylating chemotherapeutic agent.
1 . A method for treating cancer in a subject, the method comprising:
administering an anti-cancer treatment to a subject in need thereof, wherein the subject has a nucleotide excision repair (NER) deficiency score (NERDetect score) of at least 0.70 and the anti-cancer treatment comprises an alkylating chemotherapeutic agent, and
wherein the NERDetect score is a summation by logistic regression of one or more of the following mutational features of NER deficiency:
i. the number of mutations associated with a signature of insertions and deletions;
ii. the number of deletions (1-50 bp);
iii. the number of mutations associated with a signature of single base substitutions (SBS;
iv. the number of mutations associated with a signature of doublet base substitutions (DBS); and
v. the ratio of the number of base substitution on the transcribed and untranscribed strand.
2 . The method of claim 1 , wherein the alkylating chemotherapeutic agent is a platinum-based chemotherapeutic agent.
3 . The method of claim 2 , wherein the platinum-based chemotherapeutic agent selected from the group consisting of cisplatin, carboplatin, dicycloplatin, eptaplatin, iproplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, phenanthriplatin, picoplatin, satraplatin, and triplatin teranitrate.
4 . The method of claim 3 , wherein the platinum-based chemotherapeutic agent is cisplatin.
5 . The method of claim 1 , wherein the alkylating chemotherapeutic agent is selected from the group consisting of busulfan, carboplatin, carboquone, carmustine (BCNU), chlorambucil, cyclophosphamide, dacarbazine (DTIC; dimethyltriazenoimid-azolecarboxamide), hexamethylmelamine, ifosfamide, irofulven, lomustine, mechlorethamine, melphalan (L-sarcolysin), mitobronitol, nimustine, procarbazine, ranimustine, streptozocin (streptozotocin), temozolomide, thiotepa, and trofosfamide.
6 . The method of claim 4 , wherein the alkylating chemotherapeutic agent is irofulven.
7 . The method of claim 1 , wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, lung cancer, ovarian cancer, thyroid cancer, pancreatic cancer, prostate cancer, uterine cancer, testicular cancer, gastric cancer, soft tissue and osteogenic sarcomas, neuroblastoma, Wim's tumor, malignant lymphoma (Hodgkin's and non-Hodgkin's lymphoma), acute myeloblastic leukemia (AMIL), acute lymphoblastic leukemia (ALL), Kaposi's sarcoma, Ewing's tumor, refractory multiple myeloma, colon cancer, and squamous cell carcinomas of the head, neck, cervix, melanoma, and vagina.
8 . The method of claim 1 , wherein the subject is a mammal.
9 . The method of claim 1 , wherein the subject is human.
10 . The method of claim 1 , wherein the method further comprises administering an additional anti-cancer treatment.
11 . The method of claim 1 , wherein the subject has previously received an anti-cancer treatment.
12 . The method of claim 1 , wherein the subject has not previously received an anti-cancer treatment.
13 . The method of claim 1 , wherein the method further comprises receiving or obtaining results of an assay indicating the subject has a NERDetect score of at least 0.70.
14 . The method of claim 1 , wherein the method further comprises assaying a sample from the subject to determine the NERDetect score.
15 . The method of claim 14 , wherein the sample is selected from the group consisting of: cells, cell lines, histological slides, frozen core biopsies, paraffin embedded tissues, formalin fixed tissues, biopsies, whole blood, nipple aspirate, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, and bone marrow.
16 . The method of claim 14 , wherein the sample is obtained before the subject has received an anti-cancer treatment.
17 . The method of claim 14 , wherein the sample is obtained after the subject has received an anti-cancer treatment.
18 . The method of claim 14 , wherein the assay comprises detecting one or more of an indel signature ID8, an indel signature ID2, an indel signature ID10, a total number of 1-50 base pair deletions, a number of mutations associated with a signature of single base substitutions (SBS) signature 5 (COSIMIC signature 5 or Signature 5*), a number of mutations associated with a signature of single base substitutions signature 2 (SBS2), a number doublet base substitutions (DBS) signature 4 (DBS4), a transcriptional strand bias of one or more mutations, or any combination thereof.
19 . The method of claim 14 , wherein the assay comprises a step of extracting nucleic acid from the sample.
20 . The method of claim 14 , wherein the assay comprises one or more of whole genome sequencing, in situ hybridization, single nucleotide polymorphism (SNP) array, transcriptional arrays, array comparative genomic hybridization (aCGH), Southern blotting, molecular inversion probe (IP).
21 . A method of selecting a subject for anti-cancer treatment, the method comprising:
determining or obtaining a NERDetect score for the subject and selecting the subject having a NERDetect score of at least 0.70 for anti-cancer treatment, and
wherein the NERDetect score is a summation by logistic regression of one or more of the following mutational features of NER deficiency:
i. the number of mutations associated with a signature of insertions and deletions:
ii. the number of deletions (1-50 bp):
iii. the number of mutations associated with a signature of single base substitutions (SBS):
iv. the number of mutations associated with a signature of doublet base substitutions (DBS); and
v. the ratio of the number of base substitution on the transcribed and untranscribed strand.
22 . A method of predicting a response to anti-cancer treatment in a subject, the method comprising determining or obtaining a NERDetect score for the subject and a NERDetect score of at least 0.70 indicates the subject is responsive to the anti-cancer treatment, and
wherein the NERDetect score is a summation by logistic regression of one or more of the following mutational features of NER deficiency:
i. the number of mutations associated with a signature of insertions and deletions;
ii. the number of deletions (1-50 bp):
iii. the number of mutations associated with a signature of single base substitutions (SBS),
iv. the number of mutations associated with a signature of doublet base substitutions (DBS); and
v. the ratio of the number of base substitution on the transcribed and untranscribed strand.
23 . The method of claim 1 , wherein the NERDetect score is calculated according to the following formula:
p
=
1
1
+
e
-
(
β
0
+
Σ
β
i
x
i
)
,
(
Formula
1
)
wherein:
p is the NERDetect score;
β o is the intercept,
i is from 1 to the number of mutational features used;
β i is the coefficient of the mutational feature; and
x i is a mutational feature of NER deficiency.
24 . The method of claim 1 , wherein the NERDetect score is calculated according to the following formula:
p
=
1
1
+
e
-
(
β
0
+
β
1
x
1
+
β
2
x
2
+
β
3
x
3
+
β
4
x
4
)
(
Formula
2
)
wherein:
p is the NERDetect score;
β o is the intercept;
β 1 , β 2 , β 3 , and β 4 are the coefficients of the mutational features associated with NER deficiency; and
x 1 , x 2 , x 3 , and x 4 are the mutational features of NER deficiency.