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-11202779-B2
Publication Date
2021-12-21
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 disclosure relates to neoplasm treatments that target quiescent cancer cells, including cellular dormancy associated with the G0 phase of the cell cycle. Quiescent cancer cells are described as a resistance mechanism, with the quiescent-cell fraction assessed by measuring the fraction of sub-G0 phase cells in a FACS assay. The approach includes using a DYRK1 inhibitor that inhibits DYRK1A or DYRK1B kinase activity to reduce the fraction of quiescent cancer cells.
In the disclosed treatment strategy, the DYRK1 inhibitor is administered sequentially or concomitantly with an EGFR inhibitor designated as an EGFR TKI. The combination is characterized by a reduction in EC50 of the EGFR TKI in cell-based assays when the DYRK1 inhibitor is present, compared to the absence of the DYRK1 inhibitor. The disclosure further describes effects such as increased apoptosis/sub-G0 and reduced quiescent-cell fraction, supporting enhanced anti-tumor activity.
The disclosure states that additional benefits may include improved survival or recurrence delay and reduced side effects via lower EGFR TKI dosing or shorter duration. It also describes combination with radiation therapy. The document enumerates EGFR inhibitors and neoplasm types and provides examples of a DYRK1 inhibitor chemical scaffold identified as formula I, including example compounds.
Claims Coverage
The independent claim describes a treating method based on two coupled inventive requirements involving reducing quiescent cancer cell fraction by at least 10% measured by FACS sub-G0 phase fraction, and reducing EGFR TKI EC50 by at least 5-fold in cell-based assays when combined with the DYRK1 inhibitor. Dependent claims further refine the treated neoplasm type and constrain the DYRK1 inhibitor and EGFR TKI to specified sets.
DYRK1 inhibitor reduces quiescent cancer cells by sub-G0 FACS fraction
A DYRK1 inhibitor which inhibits DYRK1A or DYRK1B kinase activity that reduces the fraction of quiescent cancer cells by at least 10% as determined by fraction of sub-G0 phase cells in a FACS assay.
EGFR TKI EC50 reduced by at least 5-fold in presence of DYRK1 inhibitor
An EGFR TKI wherein EC50 of the EGFR TKI is reduced by at least 5-fold or more in cell-based assays in the presence of the DYRK1 inhibitor as compared to the absence of the DYRK1 inhibitor.
Sequentially or concomitantly administering DYRK1 inhibitor with EGFR TKI to treat neoplasm
Administering to the subject, sequentially or concomitantly, the DYRK1 inhibitor and the EGFR TKI where the subject has a neoplasm, thereby treating the subject having the neoplasm.
DYRK1 inhibitor selected from I-1 to I-7
The method includes selecting the DYRK1 inhibitor from I-1, I-2, I-3, I-4, I-5, I-6, and I-7.
EGFR TKI selected from AZD3759 and MTKi-327 (JNJ-26483327)
The method uses an EGFR TKI selected from AZD3759 and MTKi-327 (JNJ-26483327).
Reversible EGFR TKI selection
The EGFR TKI is a reversible inhibitor selected from brigatinib, CUDC-101, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, tesevatinib, Tyrphostin AG 1478, vandetanib, or varlitinib.
Irreversible EGFR TKI selection
The EGFR TKI is an irreversible inhibitor selected from afatinib, canertinib, CL-387785 (EKI-785), CNX-2006, dacomitinib, naquotinib (ASP8273), neratinib, olmutinib (HM61713), osimertinib, PD168393, pelitinib, poziotinib, TAK285, rociletinib, and WZ4002.
Across the independent and dependent claims, the coverage is centered on a neoplasm treatment method defined by combining a DYRK1A/DYRK1B kinase-inhibiting agent with an EGFR TKI, where the DYRK1 inhibitor reduces quiescent cancer cell fraction measured by FACS sub-G0 fraction and enables an at-least-5-fold EC50 reduction for the EGFR TKI in cell-based assays. Dependent claims further narrow to selected DYRK1 inhibitor I-series compounds and specified reversible or irreversible EGFR TKI sets, as well as refining the neoplasm to specified primary/metastatic cancer types.
Stated Advantages
Improved survival or recurrence delay.
Reduced side effects via lower EGFR inhibitor dosing or shorter duration.
Documented Applications
Treating a subject having a neoplasm using a combination of a DYRK1 inhibitor with an EGFR TKI, where the combination is characterized by reduction of quiescent-cell fraction and enhanced anti-tumor activity.
Use in additional combination with radiation therapy.
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