Project description:Elderly, non-fit AML/MDS patients relapsed/refractory (R/R) after HMA-based treatment represent a highly unmet clinical need, necessitating the development of age-appropriate therapies with an acceptable safety profile, e.g. with all-trans retinoic acid (ATRA). As histone demethylase LSD1 (KDM1A) is a rational therapeutic target in AML, we conducted a phase I trial with the LSD1 inhibitor tranylcypromine (TCP, dose levels [DL] 20, 40, 60, 80mg p.o. d1-28) combined with fixed-dose ATRA (45mg/m2 p.o. d10-28) and low-dose cytarabine (LDAC, 40mg s.c. d1-10). The primary endpoint was dose limiting toxicity (DLT) in the first 28 days of treatment. The aim was the determination of the maximum tolerated dose (MTD). Enrollment into DLs was performed using the rolling six design. Twenty-three patients with R/R AML and 2 with relapsed MDS were accrued, with a median age 75 years (range 62-84), after a median of two prior treatment lines (range, 1-5). Three, 6, 6 and 10 patients were allocated to DL 20, 40, 60, and 80 mg TCP, respectively, with 3, 12, 6 , 4 patients achieving the respective dose of 20, 40, 60, and 80 mg, and 3 patients on each DL being fully evaluable for MTD. TCP was administered for a median of 39.5 days (range 11-228), for >60 days in 30% of patients. No dose-limiting toxicities (DLTs) were observed at any DL, MTD could not be established. Most common adverse events > grade 3 occurring in >10% of patients were: pneumonia (16%) and febrile neutropenia (12%). No differentiation syndrome occurred. Two patients attained a partial remission; stable disease was achieved in 10 of 22 evaluable patients. Median overall survival was 62 days (range 14-325). Accompanying studies included pharmacokinetics, serial determinations of fetal hemoglobin and genes known to be regulated by LSD1 or ATRA, such as CD86, CD38 and GFI1B. Patients’ quality of life, anxiety and depression were determined before and after treatment. In conclusion, the combination of TCP with ATRA and LDAC was well feasible, even at the highest DL. Almost half of the patients attained stable disease, indicating limited cross-resistance with prior HMA treatment. Hence, studies with more potent LSD1 inhibitors appear warranted.

Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype. Two-condition experiment, ovarian cell line (SKOV-3-13) sensitive to daily oral metronomic topotecan plus pazopaniband treatemnt compared to two in- vivo selected resistant sublines from a solid tumor (called KH092-7SD) and another from ascites tumor cells (called KH092-7AS). Biological replicates: 4 independently grown and harvested cell line passages. Two technical replicate per condition (including dye swap).

Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype.

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Study of Pazopanib, Irinotecan and Cetuximab in Combination to Treat 2nd Line Metastatic Colorectal Cancer

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