Compositions and methods of use of compounds to increase cancer patient survival time
Inventors
Assignees
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Publication Number
US-9320760-B2
Publication Date
2016-04-26
Expiration Date
Abstract
The present invention discloses and claims compositions, methods of treatment, and kits which cause an increase in time of survival in cancer patients, wherein the cancer either: (i) overexpresses thioredoxin or glutaredoxin and/or (ii) exhibits evidence of thioredoxin- or glutaredoxin-mediated resistance to one or more chemotherapeutic interventions. The present invention also discloses and claims methods and kits for the administration of said compositions to properly treat cancer patients. Additionally, the present invention discloses and claims methods and kits for quantitatively determining the level of expression of thioredoxin or glutaredoxin in the cancer cells of a cancer patient, methods of using those determined levels in the initial diagnosis and/or planning of subsequent treatment methodologies for said cancer patient, as well as ascertaining the potential growth “aggressiveness” of the particular cancer and treatment responsiveness of the particular type of cancer. Further, the present invention discloses and claims novel pharmaceutical compositions, methods, and kits used for the treatment of patients with medical conditions and disease where there is the overexpression of thioredoxin and/or glutaredoxin, and wherein this overexpression is associated with deleterious physiological effects in the patients.
Core Innovation
The patent describes increasing survival time in a patient with non-small cell lung carcinoma, including adenocarcinoma, where the non-small cell lung carcinoma overexpresses thioredoxin or glutaredoxin and/or exhibits evidence of thioredoxin-mediated or glutaredoxin-mediated resistance to chemotherapeutic agents. It links the clinically relevant tumor phenotype to cytotoxic or cytostatic activity that is adversely affected by thioredoxin or glutaredoxin overexpression and/or thioredoxin-/glutaredoxin-mediated treatment resistance.
The method requires quantitatively determining thioredoxin or glutaredoxin overexpression and/or thioredoxin-/glutaredoxin-mediated treatment resistance using fluorescence in situ hybridization (FISH), nucleic acid microarray analysis, immunohistochemistry (IHC), or radioimmunoassay (RIA). The determined tumor status is used to guide administration of a Formula (I) compound to the patient in temporal relation to chemotherapy.
The patent further provides that the method comprises administering a medically-sufficient dose of a Formula (I) compound either prior to, concomitantly with, or subsequent to the administration of one or more chemotherapeutic agents whose cytotoxic or cytostatic activity is adversely affected by the quantified thioredoxin or glutaredoxin overexpression and/or the quantified thioredoxin-/glutaredoxin-mediated treatment resistance. In particular embodiments, the chemotherapeutic agents include platinum and taxane chemotherapeutic agents, and the method includes patient groups having different ethnic backgrounds.
Claims Coverage
The independent claims cover methods for increasing survival time in non-small cell lung carcinoma patients, including the adenocarcinoma subtype and groups with different ethnic backgrounds. Across the independent claims, thioredoxin/glutaredoxin status is quantitatively determined and a Formula (I) compound is administered in relation to chemotherapy whose activity is adversely affected by the quantified resistance or overexpression. The claim set includes five independent claims.
Quantitatively determining thioredoxin/glutaredoxin status
Quantitatively determining thioredoxin or glutaredoxin overexpression and/or thioredoxin-mediated or glutaredoxin-mediated treatment resistance using fluorescence in situ hybridization (FISH), nucleic acid microarray analysis, immunohistochemistry (IHC), or radioimmunoassay (RIA).
Administering a Formula (I) compound relative to adversely affected chemotherapy
Administering a medically-sufficient dose of a Formula (I) compound to the patient either prior to, concomitantly with, or subsequent to the administration of a chemotherapeutic agent or agents whose cytotoxic or cytostatic activity is adversely affected by the overexpression of thioredoxin or glutaredoxin and/or thioredoxin-mediated or glutaredoxin-mediated treatment resistance.
Non-small cell lung carcinoma patient selection
Selecting a patient with non-small cell lung carcinoma whose tumor overexpresses thioredoxin or glutaredoxin and/or exhibits evidence of thioredoxin-mediated or glutaredoxin-mediated resistance to the chemotherapeutic agent or agents used to treat said patient.
Adenocarcinoma subtype selection
Selecting a patient with the adenocarcinoma subtype of non-small cell lung carcinoma wherein the adenocarcinoma overexpresses thioredoxin or glutaredoxin and/or exhibits evidence of thioredoxin-mediated or glutaredoxin-mediated resistance to the chemotherapeutic agent or agents used to treat said patient.
Platinum and taxane chemotherapeutic agents
Administering the Formula (I) compound to the patient with non-small cell lung carcinoma either prior to, concomitantly with, or subsequent to the administration of platinum and taxane chemotherapeutic agents wherein the cytotoxic or cytostatic activity of said chemotherapeutic agents is adversely affected by the overexpression of thioredoxin or glutaredoxin and/or thioredoxin-mediated or glutaredoxin-mediated treatment resistance.
Groups with different ethnic backgrounds
Providing a method of increasing survival time in a group of patients with non-small cell lung carcinoma and having different ethnic backgrounds by quantitatively determining thioredoxin or glutaredoxin overexpression and/or thioredoxin-mediated or glutaredoxin-mediated treatment resistance and administering a medically-sufficient dose of a Formula (I) compound either prior to, concomitantly with, or subsequent to the administration of chemotherapeutic agents whose cytotoxic or cytostatic activity is adversely affected by the quantified overexpression or resistance.
Across the independent claims, the core inventive coverage is anchored in selecting non-small cell lung carcinoma patients, including adenocarcinoma and groups with different ethnic backgrounds, based on quantitatively determined thioredoxin/glutaredoxin overexpression and/or thioredoxin-/glutaredoxin-mediated treatment resistance, followed by administering a medically-sufficient dose of a Formula (I) compound in a specified temporal relationship to chemotherapy whose cytotoxic or cytostatic activity is adversely affected by that resistance or overexpression, including platinum and taxane chemotherapy in at least one independent claim.
Stated Advantages
Increasing survival time in a patient with non-small cell lung carcinoma.
Increasing survival time in an adenocarcinoma subtype of non-small cell lung carcinoma.
Increasing survival time in a group of patients with non-small cell lung carcinoma having different ethnic backgrounds.
Reduces chemotherapy-induced peripheral neuropathy.
Potentiates chemotherapy effects.
Documented Applications
Use of a Formula (I) compound in a method to increase survival time in patients with non-small cell lung carcinoma whose tumors overexpress thioredoxin or glutaredoxin and/or exhibit thioredoxin- or glutaredoxin-mediated treatment resistance to chemotherapeutic agents.
Use of a Formula (I) compound in a method to increase survival time in patients with the adenocarcinoma subtype of non-small cell lung carcinoma characterized by thioredoxin/glutaredoxin overexpression and/or thioredoxin-/glutaredoxin-mediated resistance.
Use of a Formula (I) compound in a method to increase survival time in a group of patients with non-small cell lung carcinoma having different ethnic backgrounds, where thioredoxin/glutaredoxin overexpression and/or thioredoxin-/glutaredoxin-mediated resistance is quantitatively determined.
Use of a Formula (I) compound administered prior to, concomitantly with, or subsequent to platinum and taxane chemotherapeutic agents, in a method for increasing survival time in non-small cell lung carcinoma patients with thioredoxin/glutaredoxin overexpression or mediated resistance.
Treatment of non-small cell lung carcinoma (NSCLC), including adenocarcinoma subtype, by administering Tavocept™ in relation to chemotherapy to address thioredoxin/glutaredoxin overexpression or thioredoxin-/glutaredoxin-mediated resistance.
Use in Japan Phase III and U.S. Phase II clinical trials for NSCLC reporting reduced chemotherapy-induced peripheral neuropathy and increased survival time, as well as potentiation of chemotherapy effects.
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