CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is the national phase stage of International Application PCT/CN2018/080892 filed Mar. 28, 2018, which claims priority to International Application PCT/CN2017/078548, filed Mar. 29, 2017, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention generally relates to cancer treatment.

BACKGROUND

Clinical responses to anticancer therapies are often restricted to a subset of patients. To maximize the efficiency of anticancer therapy, personalized chemotherapy based on molecular biomarkers has been proposed. However, the identification of predicative biomarkers capable of predicting response to cancer chemotherapy still remains a challenge.

Topoisomerases (topoisomerase I and II) are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phsosphodiester backbone of DNA strands during the normal cell cycle. Human DNA topoisomerase I (Top1) is an essential enzyme that relaxes DNA supercoiling during replication and transcription. The Top1-DNA intermediates, known as cleavage complexes, are transient and at low levels under normal circumstances. However, treatment with Top1 inhibitors stabilize the cleavable complexes, prevent DNA religation and induce lethal DNA strand breaks.

In recent years, topoisomerases have become popular targets for cancer chemotherapy. It is proposed that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome, leading to apoptosis and cell death. Camptothecin, a Top1 inhibitor, and its derivatives are among the most effective anticancer agents recently introduced into clinical practice. The camptothecin derivative topotecan (Hycamtin®, GlaxoSmithKline) is approved by the U.S. FDA for the treatment of ovarian and lung cancer. Another camptothecin derivative irinotecan (CPT11) is approved for the treatment of colon cancer.

Karenitecin, also known as Cositecan, is a synthetic silicon-containing agent related to camptothecin. Because of its lipophilic property, karenitecin exhibits enhanced tissue penetration and bio-availability compared to water-soluble camptothecins. Karenitecin is currently in an international Phase III clinical trial for advanced ovarian cancer patients. Karenitecin has the potential for fewer side-effects, improved efficacy, less susceptibility to drug resistance mechanisms and an improved safety profile compared to the currently marketed camptothecin drugs. Based on prior studies, Karenitecin has a lower incidence of severe diarrhea than that caused by the marketed camptothecin drug irinotecan (Camptosar®, Pfizer), and a lower incidence and severity of anemia, neutropenia and thrombocytopenia than that caused by the marketed camptothecin drug topotecan. On the other hand, previous clinical trial has demonstrated that the response rate of Karenitecin in extensively pretreated ovarian cancer is low (Kavanagh J J et al. Int J Gynecol Cancer (2008) 18(3):460-4). Therefore, there is a need for biomarkers capable of predicting response to Karenitecin.

SUMMARY OF INVENTION

In one aspect, the present disclosure provides a method for predicting karenitecin sensitivity in a patient having cancer. In one embodiment, the method comprising: measuring the levels of RNA expression of a panel of biomarkers in a tumor sample from the patient, wherein the panel of biomarkers comprises at least 6 genes selected from the group consisting of MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239, ZNF16, CORO2A, NEB, GLDC, KLK10, DCP1B, FGF18, MIR4720 and UGT1A1; comparing each of the detected levels of RNA expression of the panel of biomarkers to a corresponding predetermined reference level; and determining a likelihood of the patient being responsive to karenitecin. In one embodiment, the panel of biomarkers includes MICB, RNASEL, TNNT2, BRCA2, P2RX5 and RBL1. In one embodiment, the panel of biomarkers includes MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239 and ZNF16. In one embodiment, the panel of biomarkers comprises MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239, ZNF16, CORO2A, NEB, GLDC and KLK10. In one embodiment, the panel of biomarkers comprises MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239, ZNF16, CORO2A, NEB, GLDC, KLK10, DCP1B, FGF18, MIR4720 and UGT1A1.

In certain embodiments, the cancer described herein is gastric cancer, lung cancer or ovarian cancer.

In certain embodiments, the levels of RNA expression are measured by an amplification assay, a hybridization assay, a sequencing assay or an array.

In one embodiment, the comparing step of the method is performed by a processor of a computing device.

In one embodiment, the determining step of the method is performed by a processor of a computing device.

In one embodiment, the determining step comprises using a machine learning model. In one embodiment, the machine learning model is a gradient boosting machine model.

In one embodiment, the method described herein further comprises recommending the administration of karenitecin to the patient.

Also provided herein is a kit for detecting the level of RNA expression of a panel of biomarkers. In one embodiment, the panel of biomarkers includes at least 6 genes selected from the group consisting of MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239, ZNF16, CORO2A, NEB, GLDC, KLK10, DCP1B, FGF18, MIR4720 and UGT1A1.

The present disclosure also provides a microarray including probes for detecting the level of RNA expression of a panel of biomarkers. In one embodiment, the panel of biomarkers comprises at least 6 genes selected from the group consisting of MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239, ZNF16, CORO2A, NEB, GLDC, KLK10, DCP1B, FGF18, MIR4720 and UGT1A1.

In another aspect, the present disclosure provides a non-transitory computer readable medium having instructions stored thereon. In one embodiment, the instructions, when executed by a processor, cause the processor to: retrieve levels of RNA expression of a panel of biomarkers comprising at least 12 genes selected from the group consisting of MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239, ZNF16, CORO2A, NEB, GLDC, KLK10, DCP1B, FGF18, MIR4720 and UGT1A1, wherein the levels are obtained from a tumor sample from a patient having cancer; comparing each of the levels of RNA expression of the panel of biomarkers to a corresponding predetermined reference level; and determining a likelihood of the patient being responsive to karenitecin.

In yet another aspect, the present disclosure provides a system predicting karenitecin sensitivity in a patient having cancer. In one embodiment, the system comprises: an in vitro diagnostic kit comprising primers for detecting the level of RNA expression of a panel of biomarkers comprising at least 6 genes selected from the group consisting of MICB, RNASEL, TNNT2, BRCA2, P2RX5, RBL1, ZNF239, ZNF16, CORO2A, NEB, GLDC, KLK10, DCP1B, FGF18, MIR4720 and UGT1A1; and a non-transitory computer readable medium having instructions stored thereon. In one embodiment, the instructions, when executed by a processor, cause the processor to: retrieve the levels of RNA expression of the panel of biomarkers detected using the in vitro diagnostic kit, compare each of the levels of RNA expression of the panel of biomarkers to a corresponding predetermined reference level, and determine a likelihood of the patient being responsive to karenitecin.

