Gene expression markers for predicting overall survival in subjects treated with sipuleucel-T

Inventors

Trager, James B. • Sheikh, Nadeem A. • GuhaThakurta, Debraj • Kandadi, Harini • Fan, Li-Qun

Assignees

Dendreon Pharmaceuticals LLC

Abstract

Gene expression profiling in patients with mCRPC identifying genes that predict overall survival in response to treatment with sipuleucel-T, the method comprising the steps of (a) determining a gene expression level of a first biomarker; (b) determining a gene expression level of at least one additional biomarker different from the first biomarker; and (c) transforming the expression level of the first biomarker and the at least one additional biomarker into a first score corresponding to a probability of overall survival in response to treatment with sipuleucel-T.

Core Innovation

The invention describes gene-expression biomarker strategies for predicting overall survival response to treatment with sipuleucel-T in patients having metastatic castration-resistant prostate cancer (mCRPC). A biological sample is obtained from the patient and is selected from whole blood, peripheral blood mononuclear cells (PBMCs), circulating tumor cells (CTCs), and tumor tissue. Expression product levels of biomarkers are measured from a specified gene set, including markers such as SYNGR3, AURKC, CHI3L2, SNTB1, ZNF268, COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.

The invention determines a first composite score based on expression product levels of the measured biomarkers, where the composite score corresponds to a probability of overall survival in response to treatment with sipuleucel-T. The composite score is derived from log-transformed expression values with specified directionality across biomarkers. The score is then used together with an expression threshold that is relative to a control group of subjects that do not meet the expression threshold, by categorizing patients as having a first composite score that is higher or lower than the threshold.

The invention further links the biomarker composite score to overall survival outcomes using statistical evaluation, including Cox proportional hazards models with treatment:gene-expression interaction and Kaplan-Meier subgroup separation. Additional aspects include candidate gene discovery using Affymetrix microarrays and NanoString nCounter, with permutation-based significance and false discovery assessment, and confirmation using qPCR panel selection. An additional composite score can be derived using LASSO/ElasticNet, including an alternative 8-gene composite score comprising COL1A1, LAX1, DPPA4, CDK5RAP2, KCNQ5, ZFYVE28, DNAH11, and TAP2.

Claims Coverage

The partial claim set provided includes one independent claim. Across this independent claim, the main inventive features are captured by measuring expression products for at least two biomarkers from a specified set in a defined biological sample type, computing a composite score that corresponds to probability of overall survival response to sipuleucel-T, and administering sipuleucel-T based on whether the composite score is higher or lower than an expression threshold relative to a control group.

Overall, the independent claim covers a treatment method in which biomarker expression levels are measured in a defined mCRPC sample, a composite score corresponding to overall-survival probability in response to sipuleucel-T is computed, and sipuleucel-T is administered based on whether that composite score is above or below an expression threshold relative to a non-threshold control group.

Stated Advantages

Documented Applications