Combined treatment with an EGFR kinase inhibitor and an inhibitor of C-KIT
A technology of kinase inhibitors and compositions, applied in drug combinations, medical preparations containing active ingredients, antibody medical ingredients, etc., can solve problems such as malignant transformation
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Embodiment 1
[0138] Herein, the inventors determined the effect of combining the EGFR inhibitor erlotinib with a small molecule KIT kinase inhibitor (OSI-930 or OSI-817) to produce synergistic growth inhibition of tumor xenografts. Unlike cytotoxic chemotherapeutic agents, which often have similar toxicity, limiting their use in combination, molecular targeting agents tend to have non-overlapping toxicity profiles. Therefore, it should be clinically feasible to design mixtures of targeting agents. The synergistic capabilities of a particular combination of targeting agents can also allow for reduced doses of each single agent. Herein, it was demonstrated that the combination of a KIT kinase inhibitor and an EGFR kinase inhibitor can effectively inhibit the growth of tumor xenografts in a synergistic manner. Therefore, combining KIT kinase inhibitors with EGFR kinase inhibitors such as erlotinib will be used clinically in patients with tumors or tumor metastases.
[0139] Materials and me...
Embodiment 2
[0148] Example 2. Post-progression treatment modality
[0149] Many patients with NSCLC who initially respond to erlotinib treatment develop progressive disease during one year of treatment. Emerging clinical data suggest that continuation of erlotinib therapy may still be beneficial in patients with progressive disease even when new therapy is initiated. The mechanism of this phenomenon is still unknown. To evaluate this, preclinical models of progressive disease are used. This model utilizes NCI-H292 tumor xenografts, which initially respond very well to erlotinib treatment. However, about 30% of mice treated with erlotinib demonstrated an initial response, which then had tumor regrowth (progression) when erlotinib treatment continued.
[0150] An in vivo model of H292 tumors with reduced sensitivity to erlotinib was generated and used to study the underlying mechanisms responsible for the post-progression therapeutic phenomenon. This mouse tumor xenograft model was gene...
Embodiment 3
[0152] Example 3. Treatment after progression, GEO model
[0153] For preclinical progression post-treatment studies, GEO cells were harvested from cell culture flasks during exponential cell growth, washed twice with sterile PBS, counted and resuspended in PBS to an appropriate concentration before subcutaneously (s.c.) Implanted on the right flank of female nu / nu CD-I mice. Establish tumors to a size of 200+ / -50mm 3, followed by randomization into vehicle control or erlotinib treatment groups. After 15 days of oral dose administration of erlotinib, mice that initially responded to erlotinib (tumor growth inhibition as demonstrated above) and then started tumor regrowth (development) while still undergoing erlotinib treatment Randomized reclassification to one of the following groups, each group n = 8: 1) no treatment; 2) maintain erlotinib treatment; 3) cancel erlotinib treatment and treat with OSI-930, or 4) Erlotinib was maintained and OSI-930 was added to the regimen. ...
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