Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof

Abstract

This application relates to combination therapies including triciribine and related compounds and bortezomib and derivatives thereof analogs and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.

Description

[0001]This application is a continuation-in-part of U.S. application Ser. No. 11 / 096,082, filed Mar. 25, 2005, which claims the benefit of U.S. provisional patent application No. 60 / 557,599 filed Mar. 29, 2004, which is incorporated herein by reference.1. FIELD OF THE INVENTION[0002]This application relates to combination therapies including triciribine compounds and bortezomib and derivatives thereof and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.2. BACKGROUND OF THE INVENTION[0003]Cancer is an abnormal growth of cells. Cancer cells rapidly reproduce despite restriction of space, nutrients shared by other cells, or signals sent from the body to stop reproduction. Cancer cells are often shaped differently from healthy cells, do not function properly, and can spread into many areas of the body. Abnormal growths of tissue, called tumors, are clusters of cells that are capable of...

AI Technical Summary

Benefits of technology

[0012]The present invention provides novel therapeutic regimens of triciribine, triciribine phosphate and related compounds in combination with bortezomib and derivatives thereof and derivatives thereof to treat tumors or cancer in a subject while limiting systemic toxicity. The invention is based on the discovery that tumors or cancers, which overexpress Akt kinase are particularly sensitive to the cytotoxic effects of TCN and related compounds and a synergistic affect would arise with a combination of bortezomib salts or derivatives thereof and derivatives thereof. The inventors have determined, contrary to the prior art and experience, how to successfully use triciribine and bortezomib and derivatives thereof and derivatives thereof to treat tumors and cancer by one or a combination of (i) administering triciribine and bortezomib and salts or derivatives thereof and derivatives thereof to patients who exhibit enhanced sensitivity to the drug; (ii) use of a described dosage level that minimizes the toxicity of the drugs but yet still exhibits efficacy; or (iii) use of a described dosage regimen that minimizes the toxicity of the drugs.

[0031]In another aspect of the present invention, dosing regimens are provided that limit the toxic side effects of TCN and related compounds. In another embodiment, such dosing regimens minimize or eliminate toxic side effects, including, but not limited to, hepatoxicity, thrombocytopenia, hyperglycemia, vomiting, hypocalcemia, anemia, hypoalbunemia, myelosuppression, hypertriglyceridemia, hyperamylasemia, diarrhea, stomachitis and / or fever. In another embodiment, the administration of TCN, TCN-P, TCN-PM or related compounds provides at least a partial, such as at least 15, 20 or 30%, or complete response in vivo in at least 15, 20, or 25% of the subjects.

Problems solved by technology

Cancer cells are often shaped differently from healthy cells, do not function properly, and can spread into many areas of the body.

However, in other cases, the myeloma cells collect in many bones, forming many bone tumors.

These factors can cause numerous cellular effects, for example, they can result in overexpression of a gene product.

This in turn results in fundamental defects in cell physiology which dictate malignancy.

Current treatments of cancer and related diseases have limited effectiveness and numerous serious unintended side effects.

Despite demonstrated clinical efficacy of many anti-cancer drugs, severe systemic toxicity often halts the clinical development of promising chemotherapeutic agents.

Further, overexpression of receptor tyrosine kinases such as EGFR and their ligands such as IGF-1, Akt overexpression and / or loss of PTEN (all of which result in hyperactivation of Akt) are associated with poor prognosis, resistance to chemotherapy and shortened survival time of cancer patients.

Images