Combinations for the treatment of neoplasms using quiescent cell targeting with EGFR inhibitors
Inventors
Vilenchik, Maria • Frid, Michael • Kuznetsova, Alexandra • Gankin, Yuriy • Duey, Marc
Assignees
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Publication Number
US-10322128-B2
Publication Date
2019-06-18
Expiration Date
Abstract
The present invention provides compositions and methods for the treatment of neoplasms, in particular, by targeting of quiescent cancer cells with therapeutic agents in combination with other treatments effective against certain neoplastic conditions, in particular, anti-cancer treatment with EGFR inhibitor agents.
Core Innovation
The invention provides a method for treating a subject having a neoplasm by administering, sequentially or concomitantly, a DYRK1 inhibitor and an EGFR TKI. The DYRK1 inhibitor is defined by having Formula I, or a pharmaceutically acceptable salt or solvate thereof, with R1 and R2 substituent definitions and optional ring formation between adjacent substituent groups and intervening carbon atoms.
A related aspect specifies a DYRK1 inhibitor that inhibits DYRK1A or DYRK1B kinase activity with an IC50 of 100 nM or lower in biochemical assays. This DYRK1 inhibition is further characterized by reducing the fraction of quiescent cancer cells by at least 10%.
The method integrates the DYRK1 inhibitor with EGFR TKI administration as part of treating the neoplasm, with optional further combination including radiation therapy. The disclosed treatment focus centers on quiescent cancer cells and cellular dormancy, with effects on quiescence and apoptosis-associated readouts in the described examples.
Claims Coverage
The patent includes two independent claims, each covering sequential or concomitant treatment of a neoplasm using a DYRK1 inhibitor together with an EGFR TKI, with claim 18 additionally requiring specific biochemical potency and quiescent-cell reduction criteria. Across the independent claims, the coverage comprises structural scope for the DYRK1 inhibitor via Formula I and substituent definitions, and functional requirements for DYRK1A/DYRK1B inhibition and reduction of quiescent cancer cells.
Sequential or concomitant DYRK1 inhibitor plus EGFR TKI treatment
Administering, sequentially or concomitantly, a DYRK1 inhibitor and an EGFR TKI to treat a subject having a neoplasm, where the DYRK1 inhibitor has Formula I or a pharmaceutically acceptable salt or solvate thereof, and includes defined R1 and R2 substituent constraints.
DYRK1A/DYRK1B inhibitory potency and quiescent cancer cell fraction reduction with EGFR TKI co-administration
Administering sequentially or concomitantly to a subject having a neoplasm a DYRK1 inhibitor that inhibits DYRK1A or DYRK1B kinase activity with an IC50 of 100 nM or lower in biochemical assays and reduces the fraction of quiescent cancer cells by at least 10%, together with an EGFR TKI.
Together, the independent claims cover co-treatment regimens that pair a DYRK1 inhibitor with an EGFR TKI, where the DYRK1 inhibitor is constrained either by Formula I substituent definitions or by DYRK1A/DYRK1B biochemical potency and quantified reduction of the fraction of quiescent cancer cells.
Stated Advantages
Improved therapeutic outcomes when the DYRK1 inhibitor is administered with the EGFR inhibitor, including reduced EC50 for the EGFR inhibitor in combination.
Reduced quiescent cancer cell fraction, including disruption of quiescence via the DYRK1 inhibitor in combination with an EGFR inhibitor.
Increased apoptosis-associated measurements, including increased sub-G0/apoptotic fractions.
Optional addition of radiation therapy as part of the treatment approach.
Documented Applications
Treating a subject having a neoplasm by administering, sequentially or concomitantly, a DYRK1 inhibitor together with an EGFR TKI.
Treating a primary or metastatic neoplasm selected from the explicitly listed cancer types in the claims, including NSCLC/lung cancer and multiple other listed cancers.
Treating neoplasms with the DYRK1 inhibitor plus EGFR TKI, optionally including administering an effective amount of radiation therapy.
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