sodium stibogluconate in the mds/aml with one of the 65 defined p53 mutations

Conditions: Myelodysplastic Syndromes; Acute Myeloid Leukemia; Myeloid Malignancy; Temperature-Sensitive p53 Mutation; Sodium Stibogluconate; P53 Mutation

Summary: to evaluate the safety and effectiveness of sodium stibogluconate in the treatment of myelodysplastic syndrome/acute myeloid leukemia (mds/aml) with p53 mutation from a defined list. the list includes 65 p53 mutations that were experimentally confirmed to be pharmacologically restored with tumor-suppressive function by antimonials.

p53 is inactivated by over hundreds of diverse mutations in cancer. the investigator purposefully selected the phenotype-reversible temperature-sensitive (ts) p53 mutations for pharmacological rescue, and pertinently used p53 thermostability as readout to screen for ts p53 mutation rescue compounds. by this, the investigator identified antiparasitic drug antimonials efficiently thermostabilized the ts mutants by noncovalent binding. the antimonials met the three go-to criteria as a targeted drug-availability of co-crystal structure, structure model-compatible structure-activity relationship, and target (p53)-specificity in cells, and consequently extended survival of xenograft mouse with ts p53 mutant. under the clinical antiparasitic dosage, the antimonials effectively rescued ts p53 mutant in patient-derived primary acute myeloid leukemia cells. scan of the most frequent 815 p53 missense mutations identified 65 of them, predominantly ts mutations, as the antimonial-treatable mutations. thus, the trial aims to evaluate the safety and effectiveness of the approved antimonial-sodium stibogluconate-in the treatment of myelodysplastic syndrome/acute myeloid leukemia (mds/aml) with the 65 antimonial-treatable p53 mutants.

Eligibility criteria:
inclusion criteria: 1. pathologically confirmed myelodysplastic syndrome (mds) or acute myeloid leukemia (aml). 2. patients with one of the 65 antimonial-treatable p53 mutations with \> 5% vaf: q136p, y234h, v272m, f270v, p278a, r213l, y126h, t253n, t253i, r158l, q136e, p142f, a129d, l194r, r110p, v172g, c176f, i254n, k305r, e285d, t155p, h296d, e258g, g279v, t211a, r213p, c229y, i232f, e294k, p152r, r196p, m160t, n131s, n131h, k139n, l330h, y220n, e298q, d148e, l264r, e224d, h168p, n263h, k320n, s227c, e286d, k292t, v203a, m237r, f212l, k132q, y236s, y126s, q136h, e221a, i232s, y163h, p190t, c182y, p142l, y163s, v218e, i195s, v272a, and s106r. 3. life expectancy \>12 weeks. 4. ecog performance status \< 3. 5. aged from 18 to 75. 6. active bone marrow hyperplasia indicated by morphology. 7. normal liver and renal function, bilirubin ≤35μmol/l, asl/alt lower than 2xuln, creatinine level ≤150μmol/l. 8. normal cardiac function. 9. lung function: dyspnea ≤ ctc ae grade 1 and sao2≥ 92% in indoor air environment. 10. written informed consent. exclusion criteria: 1. confirmed cns involvement. 2. severe cardiac diseases including myocardial infarction or heart insufficiency. 3. qt interval ≥450ms on ecg. 4. with other visceral malignancy. 5. active tuberculosis or hiv(+). 6. patients with pregnancy or lactation. 7. allergic or significantly contraindicated to any drugs involved in intervention. 8. previous intolerance or allergy history to similar drugs. 9. participation at same time in another study in which investigational drugs are used. 10. any other conditions interfering the study. 11. abnormal liver function which does not meet the inclusion criteria. 12. ecog performance status ≥3, cci \>1, adl \<100. 13. aged \ 75years

Keywords: myelodysplastic syndromes acute myeloid leukemia myeloid malignancy temperature-sensitive p53 mutations sodium stibogluconate p53 precision medicine antimonial