WO2017070441A1 - Identifying and treating cancer patients who are suitable for a targeted therapy using an hdac6 inhibitor - Google Patents

Identifying and treating cancer patients who are suitable for a targeted therapy using an hdac6 inhibitor Download PDF

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WO2017070441A1
WO2017070441A1 PCT/US2016/058066 US2016058066W WO2017070441A1 WO 2017070441 A1 WO2017070441 A1 WO 2017070441A1 US 2016058066 W US2016058066 W US 2016058066W WO 2017070441 A1 WO2017070441 A1 WO 2017070441A1
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hdac6
tumor
patient
administration
gene expression
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French (fr)
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Jose Silva
Jiyang YU
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Icahn School Of Medicine At Mount Sinai
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/16—Primer sets for multiplex assays

Definitions

  • the invention relates to cancer therapy, and more particularly relates to targeted cancer therapy using an HDAC6 inhibitor. In its most immediate sense, the invention relates to identifying cancer patients who are suitable for targeted therapy using Ricolinostat.
  • HDAC6 histone deaceylase 6
  • the invention proceeds from a discovery that viability of inflammatory breast cancer (“IBC”) cells depends on the function of HDAC6 and that administration of an HDAC6 inhibitor, and particularly Ricolinostat, can inhibit proliferation of IBC cells.
  • IBC inflammatory breast cancer
  • This discovery motivated the inventors to investigate whether other cancers, and particularly other breast cancers, might also benefit from targeted therapy using an HDAC6 inhibitor such as Ricolinostat.
  • HDAC6 activity is highly increased in HDAC6-dependent cells, acting as a master regulator.
  • an algorithm has been developed to evaluate the HDAC6 activity of individual tumor samples.
  • the algorithm produces an HDAC6-score, which identifies cancers with high HDAC6 activity and which therefore are likely to depend on HDAC6 function.
  • a method of classifying likely responsiveness of a patient having a cancer tumor to administration of an HDAC6 inhibitor begins with taking a biopsy sample of the tumor and acquiring mRNA expression profiles of the tumor tissue. These expression profiles are then integrated into a gene expression database and normalized across the entire database. The normalized gene expression profiles are then input into an algorithm along with the HDAC6 signature corresponding to the type of the breast cancer tumor. The algorithm is used to generate an output that classifies the likely responsiveness of the patient to administration of an HDAC6 inhibitor.
  • the mRNA expression profiles are acquired usaing using standard RNA-Seq technology or microarray, the gene expression database is The Cancer Genome Atlas, and the algorithm is
  • HT is the HDAC6 signature specific for tumor type T, which contains M genes, and wherein the output s is the HDAC6-score.
  • the patient is classified as sensitive to administration of an HDAC6 inhibitor when s > 1, medium sensitive to administration of an HDAC6 inhibitor when 0 ⁇ s ⁇ 1, and resistant to administration of an HDAC6 inhibitor when s ⁇ 0.
  • the cancer when the cancer is a breast cancer and particularly when the cancer is inflammatory breast cancer and the patient is sensitive or medium sensitive to administration of an HDAC6 inhibitor, the patient is treated with an HDAC6 inhibitor and particularly with Ricolinostat.
  • Fig. 1A shows overlap of the HDAC6 regulons in different tumor types.
  • Fig. 1B left panel shows HDAC6 activity score inferred by expression of the HDAC6 regulon upon
  • Fig. 1B right panel shows the expression change of the HDAC6 regulon network upon Ricolinostat treatment.
  • Node is color-coded by z-score transformed expression.
  • Fig. 1C dot-plots show the HDAC6-scores and HDAC6 expression in the primary tumor series.
  • Fig. 2A shows HDAC6-scores of primary breast cancer samples.
  • the red line represents the average HDAC6-score for IBCs.
  • Fig. 2B left panel shows the strong association between HDAC6-score and the response to the leading HDAC6 inhibitor Ricolinostat.
  • Fig. 2B right panel summarizes the result and the molecular subtype of the breast cancer lines analyzed.
  • HDAC6 function has been determined to be essential to maintain IBC cell viability and that Ricolinostat (ACY1215) controls IBC cell proliferation both in vitro and in vivo.
  • Ricolinostat ACY1215.
  • Margolin, A. A. et al. ARACNE an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context.
  • GO term enrichment analysis showed that this list was enriched in genes involved in canonical HDAC6 functions such as response to unfolded protein-induced stress (Kawaguchi, Y. et al. The
  • HDAC6 deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.
  • the expression of all transcripts of the HDAC6 regulon was integrated into a single score (termed the HDAC6-score) by summarizing their expression values using a ‘maxmean’ statistic (Efron, B. & Tibshirani, R. On Testing the Significance of Sets of Genes. Ann Appl Stat 1, 107-129, doi:Doi 10.1214/07-Aoas101 (2007); Rodriguez- Barrueco, R. et al. Inhibition of the autocrine IL-6- JAK2-STAT3-calprotectin axis as targeted therapy for HR- /HER2+ breast cancers. Genes & development,
  • the HDAC6-score, s is computed as follows:
  • P is a normalized gene expression profile
  • Pi represents the expression value for gene I
  • HT is the HDAC6 signature specific for tumor type T, which contains M genes.
  • HDAC6-score is an indicator of the HDAC6 activity
  • HDAC6-dependent breast cancer cells were treated with Ricolinostat and the HDAC6-score was compared.
  • HDAC6 score was evaluated in a series of primary tumors. This evaluation revealed that IBCs had a significantly higher HDAC6-score than non-IBCs (Fig. 1C).
  • HDAC6-score was calculated for approximately 1000 primary breast cancers with available expression profile data (BRCA-TCGA (Cancer Genome Atlas, N. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70, doi:10.1038/nature11412 (2012)) data set). This study revealed that approximately 15-20% of all breast cancers (enriched in hormone receptor positive (HR+) and HER2 positive (HER+)) had HDAC6-scores higher than the average HDAC6-score of the IBCs which suggests that these tumors may be sensitive to HDAC6 inhibitors (Fig. 2A).
  • the highest HDAC6-score was found in luminal and HER2+ breast cancer cells (Fig. 2B).
  • Ricolinostat (ACY-1215) is commercially available from Acetylon Pharmaceuticals (Boston MA). It is a liquid that is administered systemically using the oral route but other routes of administration may be used instead. A therapeutically effective dose is presently believed to be 80 mg – 240 mg/day for 21 days but other dosages and schedules can be used instead. As stated above, it has been shown that
  • treating and “treatment,” as used herein, refer to administering to a patient having inflammatory breast cancer a therapeutically effective dose of an HDAC6 inhibitor such as Ricolinostat.
  • HDAC6 inhibitor such as Ricolinostat.
  • the term “treating” covers any treatment of inflammatory breast cancer that results in a desired pharmacologic and/or physiologic effect, including arresting disease development, causing regression of the disease, limiting spread of the cancer from one cell to another within an individual, and limiting replication of cancer cells within an individual.
  • terapéuticaally effective dose refers to an amount of a pharmaceutical that results in an
  • a therapeutically effective dose of an HDAC6 inhibitor such as Ricolinostat minimizes the onset of, or hastens or increases recovery of a subject from, inflammatory breast cancer.
  • an HDAC6 inhibitor such as Ricolinostat may provide a therapeutic benefit in the treatment or management of inflammatory breast cancer by reducing the spread of the cancer within the patient and may also prevent disease and/or reduce the severity of symptoms.
  • a therapeutically effective dose can be determined by the skilled person as a matter of routine experimentation.
  • the therapeutically effective dosage of the pharmaceutical composition can be determined readily by the skilled artisan, for example, from animal studies.
  • human clinical studies can be performed to determine the preferred effective dose for humans by a skilled artisan. Such clinical studies are routine and well known in the art.
  • the precise dose to be employed will also depend on the route of administration.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal test systems.

Abstract

It has been discovered that proliferation of inflammatory breast cancer (IBC) cells can be inhibited by inhibiting the function of histone deacetylase 6 (HDAC6). Advantageously, such functional inhibition is accomplished by administration of a therapeutically effective dose of Ricolinostat (ACY1215) to a patient in whom IBC cells are proliferating. In further accordance with the invention, it is possible to predict the responsiveness of a particular patient with cancer (particularly breast cancer, and most specifically inflammatory breast cancer) to administration of an HDSC6 inhibitor. This is accomplished by acquiring mRNA gene expression profiles of a biopsy sample of the patient's tumor tissue. The processed gene expression profiles of the patient are then integrated into a gene expression database and are then normalized across the entire database. Then, the normalized gene expression profiles are input to an algorithm. An HDAC6 signature characteristic of the patient's tumor type is also input to the algorithm, and the output of the algorithm makes it possible to evaluate the responsiveness of the patient's tumor to administration of HDAC6 inhibitor. Advantageously, the gene expression profiles are acquired using standard RNA-Seq technology or microarray and the gene expression database is The Cancer Genome Atlas ("TCGA").

Description

IDENTIFYING AND TREATING CANCER PATIENTS WHO ARE SUITABLE FOR A TARGETED THERAPY USING AN HDAC6 INHIBITOR
The invention relates to cancer therapy, and more particularly relates to targeted cancer therapy using an HDAC6 inhibitor. In its most immediate sense, the invention relates to identifying cancer patients who are suitable for targeted therapy using Ricolinostat.
It is known that viability of certain cancer cells requires functioning of histone deaceylase 6 (“HDAC6”), and certain small molecule HDAC6 inhibitors are now in clinical trials. However, it has up to now been
impossible to predict whether a particular patient with a particular cancer will respond to therapy by
administration of an HDAC6 inhibitor.
It would be advantageous to provide a method by which the likely response of a particular cancer patient with a particular tumor could be classified as sensitive, medium sensitive, or resistant to targeted therapy using an HDAC6 inhibitor, before treating the patient.
The invention proceeds from a discovery that viability of inflammatory breast cancer (“IBC”) cells depends on the function of HDAC6 and that administration of an HDAC6 inhibitor, and particularly Ricolinostat, can inhibit proliferation of IBC cells. This discovery motivated the inventors to investigate whether other cancers, and particularly other breast cancers, might also benefit from targeted therapy using an HDAC6 inhibitor such as Ricolinostat.
Such investigation revealed that HDAC6 activity is highly increased in HDAC6-dependent cells, acting as a master regulator. And, in accordance with the invention, an algorithm has been developed to evaluate the HDAC6 activity of individual tumor samples. The algorithm produces an HDAC6-score, which identifies cancers with high HDAC6 activity and which therefore are likely to depend on HDAC6 function.
In accordance with the invention, a method of classifying likely responsiveness of a patient having a cancer tumor to administration of an HDAC6 inhibitor begins with taking a biopsy sample of the tumor and acquiring mRNA expression profiles of the tumor tissue. These expression profiles are then integrated into a gene expression database and normalized across the entire database. The normalized gene expression profiles are then input into an algorithm along with the HDAC6 signature corresponding to the type of the breast cancer tumor. The algorithm is used to generate an output that classifies the likely responsiveness of the patient to administration of an HDAC6 inhibitor.
Advantageously, the mRNA expression profiles are acquired usaing using standard RNA-Seq technology or microarray, the gene expression database is The Cancer Genome Atlas, and the algorithm is
Figure imgf000003_0001
represents the expression value for gene I, HT is the HDAC6 signature specific for tumor type T, which contains M genes, and wherein the output s is the HDAC6-score.
In further accordance with the invention, the patient is classified as sensitive to administration of an HDAC6 inhibitor when s > 1, medium sensitive to administration of an HDAC6 inhibitor when 0 ≤ s ≤ 1, and resistant to administration of an HDAC6 inhibitor when s < 0.
Advantageously, when the cancer is a breast cancer and particularly when the cancer is inflammatory breast cancer and the patient is sensitive or medium sensitive to administration of an HDAC6 inhibitor, the patient is treated with an HDAC6 inhibitor and particularly with Ricolinostat.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood with reference to the following exemplary and non-limiting drawings, in which:
Fig. 1A shows overlap of the HDAC6 regulons in different tumor types.
Fig. 1B left panel shows HDAC6 activity score inferred by expression of the HDAC6 regulon upon
treatment with Ricolinostat.
Fig. 1B right panel shows the expression change of the HDAC6 regulon network upon Ricolinostat treatment. Node is color-coded by z-score transformed expression. Edge is coded by the Pearson correlation of HDAC6 and corresponding regulon node (red=:+, blue=-).
Fig. 1C dot-plots show the HDAC6-scores and HDAC6 expression in the primary tumor series.
Fig. 2A shows HDAC6-scores of primary breast cancer samples. The red line represents the average HDAC6-score for IBCs.
Fig. 2B left panel shows the strong association between HDAC6-score and the response to the leading HDAC6 inhibitor Ricolinostat.
Fig. 2B right panel summarizes the result and the molecular subtype of the breast cancer lines analyzed.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS HDAC6 function has been determined to be essential to maintain IBC cell viability and that Ricolinostat (ACY1215) controls IBC cell proliferation both in vitro and in vivo. (See Putcha, P. et al. HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers. Breast Cancer Res 17, 149, doi:10.1186/s13058- 015-0658-0 (2015), which is hereby incorporated herein by reference as if fully set forth).
The gene expression profiles from approximately 1000 breast cancer samples available in the The Cancer Genome Atlas BRCA data set (Cancer Genome Atlas, N.
Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70, doi:10.1038/nature11412 (2012)) were used to reconstruct the genome-wide
regulatory networks of breast cancer cells using the ARACNe algorithm (Carro, M. S. et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318-325, doi:10.1038/nature08712 (2010);
Margolin, A. A. et al. ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context. BMC Bioinformatics 7 Suppl 1, S7, doi:1471-2105-7-S1-S7 [pii]). These methods identified a regulon consisting of 162 transcripts whose expression is regulated by HDAC6 activity. GO term enrichment analysis showed that this list was enriched in genes involved in canonical HDAC6 functions such as response to unfolded protein-induced stress (Kawaguchi, Y. et al. The
deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727-738 (2003); Matthias, P., Yoshida, M. &
Khochbin, S. HDAC6 a new cellular stress surveillance factor. Cell cycle 7, 7-10 (2008); Boyault, C. et al. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev 21, 2172- 2181, doi:10.1101/gad.436407 (2007)). Analysis of lung cancer (TCGA LUAD) specific and colorectal cancer (TCGA COAD-READ) specific HDAC6 regulons showed that the overlap with the breast cancer regulon was highly significant (Fig. 1A). This suggested that the transcriptional footprint of HDAC6 is highly conserved among epithelial cancer cells.
Next, the expression of all transcripts of the HDAC6 regulon was integrated into a single score (termed the HDAC6-score) by summarizing their expression values using a ‘maxmean’ statistic (Efron, B. & Tibshirani, R. On Testing the Significance of Sets of Genes. Ann Appl Stat 1, 107-129, doi:Doi 10.1214/07-Aoas101 (2007); Rodriguez- Barrueco, R. et al. Inhibition of the autocrine IL-6- JAK2-STAT3-calprotectin axis as targeted therapy for HR- /HER2+ breast cancers. Genes & development,
doi:10.1101/gad.262642.115 (2015)).
The HDAC6-score, s, is computed as follows:
Figure imgf000006_0001
wherein P is a normalized gene expression profile, Pi represents the expression value for gene I, and HT is the HDAC6 signature specific for tumor type T, which contains M genes.
To demonstrate that the HDAC6-score is an indicator of the HDAC6 activity, HDAC6-dependent breast cancer cells were treated with Ricolinostat and the HDAC6-score was compared. As expected, inhibition of HDAC6
significantly attenuated the HDAC6-score (Fig. 1B).
Finally, the HDAC6 score was evaluated in a series of primary tumors. This evaluation revealed that IBCs had a significantly higher HDAC6-score than non-IBCs (Fig. 1C).
The data revealed that dependency on HDAC6 function was linked to its high activity. It was reasoned that additional breast cancers, other than IBCs, could present the same dependency. To investigate this possibility the HDAC6-score was calculated for approximately 1000 primary breast cancers with available expression profile data (BRCA-TCGA (Cancer Genome Atlas, N. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70, doi:10.1038/nature11412 (2012)) data set). This study revealed that approximately 15-20% of all breast cancers (enriched in hormone receptor positive (HR+) and HER2 positive (HER+)) had HDAC6-scores higher than the average HDAC6-score of the IBCs which suggests that these tumors may be sensitive to HDAC6 inhibitors (Fig. 2A). An independent validation study using the Metabric (Pai, J. T. et al. NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells. Molecules 20, 8000-8019,
doi:10.3390/molecules20058000 (2015)) data set containing ~2,000 primary breast cancer showed identical results (data not shown).
The studies were than transitioned to experimental models. The HDAC6-score and the response to Ricolinostat were evaluated in fourteen breast cancer cell lines representing all molecular subtypes (Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346- 352, doi:10.1038/nature10983 (2012)). Remarkably, there was a very high correlation between response to treatment (low IC50) and high HDAC6-score (high HDAC6 activity) (Fig. 2B). Furthermore, in agreement with the data from primary tumors, the highest HDAC6-score was found in luminal and HER2+ breast cancer cells (Fig. 2B).
Ricolinostat (ACY-1215) is commercially available from Acetylon Pharmaceuticals (Boston MA). It is a liquid that is administered systemically using the oral route but other routes of administration may be used instead. A therapeutically effective dose is presently believed to be 80 mg – 240 mg/day for 21 days but other dosages and schedules can be used instead. As stated above, it has been shown that
proliferation of IBC cells can be inhibited by
administration of an HDAC6 inhibitor, and particularly Ricolinostat. To a person of ordinary skill in the art, this is convincing evidence that administration of a therapeutically effective dose of an HDAC6 inhibitor, and particularly Ricolinostat, can be used to treat a patient with inflammatory breast cancer.
The terms "treating" and "treatment," as used herein, refer to administering to a patient having inflammatory breast cancer a therapeutically effective dose of an HDAC6 inhibitor such as Ricolinostat. As used herein, the term “treating” covers any treatment of inflammatory breast cancer that results in a desired pharmacologic and/or physiologic effect, including arresting disease development, causing regression of the disease, limiting spread of the cancer from one cell to another within an individual, and limiting replication of cancer cells within an individual.
The term "therapeutically effective dose” refers to an amount of a pharmaceutical that results in an
improvement or remediation of the symptoms of a disease or condition to be treated. A therapeutically effective dose of an HDAC6 inhibitor such as Ricolinostat minimizes the onset of, or hastens or increases recovery of a subject from, inflammatory breast cancer. A
therapeutically effective dose of an HDAC6 inhibitor such as Ricolinostat may provide a therapeutic benefit in the treatment or management of inflammatory breast cancer by reducing the spread of the cancer within the patient and may also prevent disease and/or reduce the severity of symptoms.
A therapeutically effective dose can be determined by the skilled person as a matter of routine experimentation. The therapeutically effective dosage of the pharmaceutical composition can be determined readily by the skilled artisan, for example, from animal studies. In addition, human clinical studies can be performed to determine the preferred effective dose for humans by a skilled artisan. Such clinical studies are routine and well known in the art. The precise dose to be employed will also depend on the route of administration.
Effective doses may be extrapolated from dose-response curves derived from in vitro or animal test systems.
Although preferred embodiments of the invention have been disclosed above, the scope of the invention is limited only by the following claims:

Claims

1. A method of classifying likely responsiveness of a patient having a cancer tumor to administration of an HDAC6 inhibitor, comprising:
a. taking a biopsy sample of the tumor;
b. acquiring mRNA expression profiles of the tumor tissue, integrating them into a gene expression database and normalizing them across the entire database;
c. inputting into an algorithm the
i. normalized gene expression profiles, and ii. the HDAC6 signature corresponding to the type of the cancer tumor;
d. using the algorithm to generate an output; and e. using the output to classify the likely
responsiveness of the patient to administration of an HDAC6 inhibitor.
2. The method of claim 1, wherein the acquiring step is carried out using standard RNA-Seq technology or microarray.
3. The method of claim 1, wherein the gene expression database is The Cancer Genome Atlas.
4. The method of claim 1, wherein the algorithm is
Figure imgf000010_0001
wherein P is a normalized gene expression profile, Pi represents the expression value for gene I, HT is the HDAC6 signature specific for tumor type T, which contains M genes, and wherein the output s is the HDAC6-score.
5. The method of claim 1, wherein the patient is classified as:
a. sensitive to administration of an HDAC6
inhibitor when s > 1;
b. medium sensitive to administration of an HDAC6 inhibitor when 0 ≤ s ≤ 1; and
c. resistant to administration of an HDAC6
inhibitor when s < 0.
6. The method of claim 1, wherein the tumor is a breast cancer tumor.
7. The method of claim 1, wherein the breast cancer tumor is an inflammatory breast cancer tumor.
8. The method of claim 1, wherein the tumor is a breast cancer tumor.
9. The method of claim 1, wherein the tumor is an
inflammatory breast cancer tumor.
10. A method of identifying and treating a cancer patient who is suitable for a targeted cancer therapy using an HDAC6 inhibitor, comprising:
a. taking a biopsy sample of the tumor;
b. acquiring mRNA expression profiles of the tumor tissue, integrating them into a gene expression database and normalizing them across the entire database;
c. inputting into an algorithm the
i. normalized gene expression profiles, and ii. the HDAC6 signature corresponding to the type of the cancer tumor; d. using the algorithm to generate an output;
e. using the output to classify the likely
responsiveness of the patient to administration of an HDAC6 inhibitor; and
f. administering a therapeutically effective dose HDAC6 inhibitor to the patient only if the patient is classified as sensitive or medium sensitive to administration or an HDAC6 inhibitor.
11. The method of claim 1, wherein the tumor is a breast cancer tumor.
12. The method of claim 1, wherein the breast
cancer tumor is an inflammatory breast cancer tumor.
13. The method of claim 1, wherein the HDAC6
inhibitor is Ricolinostat.
14. The method of claim 1, wherein the HDAC6
inhibitor is Ricolinostat.
15. The method of claim 1, wherein the algorithm is
Figure imgf000012_0001
wherein P is a normalized gene expression profile, Pi represents the expression value for gene I, HT is the HDAC6 signature specific for tumor type T, which contains M genes, and wherein the output s is the HDAC6-score.
16. The method of claim 1, wherein the patient is classified as: a. sensitive to administration of an HDAC6 inhibitor when s > 1;
b. medium sensitive to administration of an HDAC6 inhibitor when 0 ≤ s ≤ 1; and
c. resistant to administration of an HDAC6
inhibitor when s < 0.
PCT/US2016/058066 2015-10-23 2016-10-21 Identifying and treating cancer patients who are suitable for a targeted therapy using an hdac6 inhibitor WO2017070441A1 (en)

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