Lead Inventor:
Adolfo A. Ferrando, M.D., Ph.D.
Tech Ventures Reference: IR 2074, 2075, 2076
Problem or Unmet Need:
Constitutively active forms of the receptor NOTCH-1 contribute to over 50% of human T-Cell lymphoblastic leukemias and lymphomas (T-ALLs) and may play an additional role in the pathogenesis of solid tumors, such as breast carcinomas, gliomas and neuroblastomas. The use of glucocorticoids or inhibitors of NOTCH-1 that target gamma-secretase has been effective in inhibiting cancer growth, but in some cases the cancer is resistant to treatment. Additionally, upon relapse the cancer is often resistant to the previously effective therapy. In these resistant cases the prognosis is very poor. With 5 year survival rates being 80% in children and only 40% in adults there is a clear need for an effective diagnosis and treatment of these resistant cancer variants.
Details of the Invention:
This technology details both therapies for T-ALLs resistant to standard chemotherapy treatments and methods for determining the mutation status of the cancer. Cancers resistant to glucocorticoids alone were treated with glucocorticoids paired with gamma secretase inhibitors (GSIs) or AKT protein inhibitors. It was shown that resistance of cell lines to glucocorticoids was reversed when combined with GSIs. Also, cell lines, which showed both GSI and glucocorticoid resistance, were susceptible to treatment with the combinatorial glucocorticoid/GSI regimen. In addition, the technology outlined the methods for determining the mutation status of the PTEN gene: DNA extraction and sequencing, hybridization to known PTEN polynucleotides (with and without mutations), or reverse transcriptase PCR. After the mutation status was determined this technology could indicate whether the patient will be resistant to gamma-secretase inhibitors or sensitive to AKT inhibitors.
Applications:
• Diagnosis of cancer patients to aid in treatment decisions
• Design of clinical trials for drugs specific to certain cancers
• Treatment of initially glucocorticoid or GSI resistant T-ALLs, and in the case of a relapse, treatment of resistant disease which was previously responsive to either treatment
• Treatment of T-ALL resistant to both glucocorticoids and to second line treatment with GSIs
• Treatment of other chemotherapy resistant cancers, including tumorogenic types such as breast and ovarian cancer
Advantages:
• Previously untreatable cancers can be arrested by combining glucocorticoids with GSIs. The new treatment course could significantly improve the 5-year survival rate.
• The combinatorial treatment regimen could also be applied to chemotherapy resistant tumorogenic cancers such as breast or ovarian cancer similarly rendering previously untreatable cancers of these varieties curable.
• Methods of determining mutation status of patient facilitate the design of superior treatment plans.
• Mutation status diagnosis allows for more effective mutation-specific drug design and testing.
Patent Status: Patent Pending (WO/2008/094709, WO/2009/005688, WO/2008/112249) ~ see links below.
Licensing Status: Available for Licensing and Sponsored Research Support
Publications:
Palomero T, Dominguez M, Ferrando AA. The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia. Cell Cycle. 2008 Apr 15;7(8):965-70.
Patent No. 8,633,179