经修饰的GHRH拮抗剂醋酸盐形式保留了针对急性髓系白血病的抗白血病活性

Acute myeloid leukemia (AML) is a heterogenous hematological malignancy characterized by an accumulation of immature myelocytic cells resulting from aberrancies to programs underlying the survival, proliferation, and maturation of myeloid progenitor cells during hematopoiesis. Despite continuous improvement in AML therapies, five-year survival rates remain at 31.7%, and standard induction therapy relies on the use of intense chemotherapeutic regimes, followed by HSCT if applicable. This underscores the need for novel therapies, ideally without introducing adverse events as side effects to treatment. GHRH antagonists, represent a new therapeutic modality and pre-clinically have shown robust activity against various cancer types with minimal peripheral toxicity. Previously we demonstrated MIA-602, a GHRH antagonist, to have significant anti-leukemic activity both in-vitro and in-vivo against APL and an all-trans retinoic acid/arsenic trioxide (RAA) resistant clone, as well as AML and a doxorubicin resistant (DR) clone. When MIA-602 was combined with standard therapy in non-resistant models, the anti-leukemic effect produced was made even more potent. Whilst in resistant models, MIA-602 monotherapy retained its significant anti-leukemic activity, implying a distinct mechanism of action independent from that of traditional therapeutic modalities. Here we tested a more clinically acceptable acetate salt form of MIA-602, MIA-602 Ac, and showed that it retained significant anti-leukemic activity against both APL and AML in-vitro as well as versus their RAA and DR analogs, respectively. In order to assess retention of MIA-602Ac's anti-leukemic efficacy, NB4 and NB4-RAA cells, were cultured with increasing doses of MIA-602Ac ranging from 0.05 to 5 μmol/L. K562 and K562-DR cells, were cultured with MIA-602Ac alone or combined with doxorubicin at varying concentrations ranging from 0.05 to 5 μmol/L and 0.005 to 0.05 μg/ml respectively, using doxorubicin as the standard-of-care comparator. Cell viability was measured 24h and 48h post-treatment. Our results show that MIA-602Ac maintained a significant dose- and time-dependent anti-leukemic effect as seen previously with MIA-602. Synergism of GHRH antagonism with standard of care therapies was preserved. MIA-602Ac as a monotherapy could still produce significant anti-leukemic effects in resistant cell lines. In conclusion, further clinical investigation of MIA-602Ac as a monotherapy, or adjuvant therapy for the treatment of acute myeloid leukemia is warranted, given its continued preclinical success and improvements made to toxicity.