Citations

Abstract Background nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), using intraliposomal stabilisation technology to enable high drug load and in-vivo stability. The expansion of Phase I NCT01770353 evaluated nal-IRI in patients (pts) with mBC. Methods This Phase I expansion study enrolled mBC pts (Cohort 1: ER+ and/or PR+ HER2 BC (C-1); Cohort 2: Triple Negative BC (TNBC, C-2); Cohort 3: BC with active Brain Metastasis (C-3)). Key inclusion criteria: ECOG ≤1; adequate organ function; received >1 to ≤5 prior lines of cytotoxic therapy in metastatic setting, except TNBC pts who could have progressed within 12 months of adjuvant therapy. Pts received nal-IRI 50 mg/m2 (Free-base equivalent, FBE) q2w iv infusion, escalating to 70 mg/m2 FBE q2w, if tolerated. Results 30 pts (10 per cohort) were enrolled: 29 received >1 dose nal-IRI 50 mg/m2 FBE (median age 53 yrs, range 29-70 yrs). Median number of cytotoxic therapies prior to study entry was 3. The most frequent treatment emergent adverse events (TEAEs) were gastrointestinal disorders (all cohorts, 100%), primarily diarrhea (C-1, 100% / C-2, 100% / C-3, 70%), nausea (C-1, 80% / C-2, 56% / C-3, 30%), and vomiting (C-1, 60% / C-2, 33% / C-3, 30%). The incidence of neutropenia was low (C-1, 10% / C-2, 0% / C-3, 10%), all grade 1 / 2. Most common grade 3 TEAEs were diarrhea (28%), nausea (17%), fatigue (14%), hypokalemia (10%) and asthenia (10%), with none reported as grade 4. No grade 5 TEAEs were reported. Partial response (per RECIST) was observed in 10 pts for an objective response rate (ORR) of 35% (C-1, 40% / C-2, 33%) / C-3, 30%). Stable disease was observed in 5 pts (17%). Duration of Response (median, months) was C-1, 7.5 (6.4-13.0) / C-2, 5.6 (3.7-7.4) / C-3, 4.1 (0.0-22.2, extracranial: RECIST) / C-3, 1.8 (0.0-1.9, intracranial: mRECIST). Table 1.Study Demographics, Adverse Events, and Best Overall ResponseDemographicsCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=10Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=30Gender, Female, n (%)10 (100%)10 (100%)10 (100%)30 (100%)Age, Years Median (range)56 (49-68)52.5 (37-70)45.5 (29-63)53 (29-70)Race, n (%)WhiteBlack/AfricanOther8 (80%)02 (20%)8 (80%)1 (10%)1 (10%)7 (70%)1 (10%)2 (20%)23(77%)2 (7%)5(16%)Months Since Metastatic diagnosis, Months Median (Range)63.7 (16-87)20.7 (0-34)32.4 (8-55)24.0 (0-87)Number of Prior Cytotoxic Anti-cancer Regimens Median (Range)3.0 (1-6)3.0 (0-5)32.4 (1-6)3.0 (0-6)Safety PopulationCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=9Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=29ExposureTreatment Duration, Weeks Median (range)6.1 (0-78)12.3 (0-49)13.9 (1-105)12.3 (0-105)Adverse EventsAny TEAE10 (100%)9 (100%)10 (100%)29 (100%)Grade 38 (80%)6 (67%)10 (100%)20 (69%)Grade 41 (10%)06 (60%)3 (10%)TEAE Related to nal-IRI10 (100%)8 (89%)10 (100%)28 (97%)Grade > 36 (60%)3 (33%)3 (30%)12 (41%)TEAE Related to nal-IRILeading to Dose Adjustment*7 (70%)3 (33%)4 (40%)14 (48%)SAEs6 (60%)4 (44%)7 (70%)17 (59%)SAE Related to nal-IRI4 (40%)1 (11%)1 (10%)6 (21%)Duration of Objective ResponseRECIST 1.1RECIST 1.1RECIST 1.1mRECISTMonths Median (Range)7.5 (6.4-13.0)5.6 (3.7-7.4)4.1 (0.0-22.2)1.84 (0.0-1.9)Best Overall ResponseRECISTRECISTRECISTmRECISTComplete Response (CR)0000Partial Response (PR)4 (40%)3 (33%)3 (30%)3 (30%)Stable Disease (SD)03 (33%)2 (20%)3 (30%)Progressive Disease (PD)5 (50%)2 (22%)3 (30%)2 (20%)Not Evaluable (NE)1 (10%)1 (11%)2 (20%)2 (20%)Objective Response RateCR+PR(95% CI)4 (40%)12.2 -73.83 (33%)7.5-70.73 (30%)6.7-65.33 (30%)(6.7-65.3)*n=1 patient in Cohort 1 discontinued treatment due to TEAE related to treatment with nal-IRI CI, Confidence Interval; nal-IRI, Irinotecan Liposome Injection; SAE, Serious Adverse Event; TEAE, Treatment Emergent Adverse EventSystemic tumor response was evaluated according to RECIST version 1.1CNS tumor response was evaluated according to mRECIST (Anders C. et al., Breast Cancer Res Treat, 2014: 146(3):557-66) Conclusion nal-IRI monotherapy 50g/m2 FBE Q2W appears well tolerated, and achieved >30% ORR for systemic and CNS disease among heavily pre-treated mBC pts regardless of receptor status. Citation Format: Jasgit Sachdev, Pamela Munster, Donald Northfelt, Hyo S. Han, Cynthia MA, Fiona Maxwell, Tiffany Wang, Bruce Belanger, Bin Zhang, Yan Moore, Carey Anders. Phase I expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT048.

Abstract The presence of FMS-like receptor tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate primitive FLT3-ITD+ leukemia cells, which are potential sources of relapse. Thus, understanding the mechanisms underlying FLT3-ITD+ AML cell persistence is essential to devise future AML therapies. Here, we show that expression of protein arginine methyltransferase 1 (PRMT1), the primary type I arginine methyltransferase, is increased significantly in AML cells relative to normal hematopoietic cells. Genome-wide analysis, coimmunoprecipitation assay, and PRMT1-knockout mouse studies indicate that PRMT1 preferentially cooperates with FLT3-ITD, contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD+ AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginine 972/973, and PRMT1 promoted leukemia cell growth in an FLT3 methylation–dependent manner. Moreover, the effects of FLT3-ITD methylation in AML cells were partially due to cross talk with FLT3-ITD phosphorylation at tyrosine 969. Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following kinase inhibition, indicating that methylation occurs independently of kinase activity. Finally, in patient-derived xenograft and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML cells relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to eliminate FLT3-ITD+ AML cells.

The cardiology diagnostic are the methods of identifying current or past heart conditions, which can advise caregivers on patient diagnosis and provide a proper therapy plan, nowadays couple new diagnostic methods have been developed and some of them like radionuclide myocardial perfusion imaging, coronary computed tomography angiogram, cardiac magnetic resonance imaging, intravascular ultrasonography, optical coherence tomography, intravascular thermography, intravascular elastography, and near-infrared spectroscopy have been approved for clinical use. Not only the advanced technologies, the new biomarkers, and genetic markers may provide new potential targets for the diagnosis, therapy, and prevention of heart diseases.

The balance between local asymmetric dimethylarginine (ADMA) levels and dimethylarginine dimethylaminohydrolase 1 (DDAH1) activity is a major determinant of local nitric oxide synthase activity. Previous studies suggested that increased plasma ADMA levels are strongly associated with the aortic valve stenosis, causal or mechanistic links have yet to be elucidated. Thus, the aim of this study was to investigate whether reduction or overexpression of DDAH1 protects aortic valve dysfunction in mice. To experimentally alter DDAH1 levels, we used low density lipoprotein receptor deficient, apolipoprotein B100-only (LA) mice that were either DDAH1 wild-type (D +/+ or D 0/0 ), heterozygous (D +/- ), or transgenic/overexpressing (D Tg/0 ) littermates. All mice were fed a western diet for 6 months. Reducing DDAH1 increased plasma ADMA levels (LA-D +/+ =0.89 ± 0.02 μmol/L, LA-D +/- =1.1 ± 0.02 μmol/L, p< 0.05) and blood pressure (LA-D +/+ = 125 ± 4 mmHg, LA-D +/- = 141 ± 3 mmHg, p< 0.05) following 6 months of western diet feeding. Critically, aortic valve function was significantly worse in DDAH1-deficient mice (LA-D +/+ 2.20±0.09 m/sec versus LA-D +/- =2.41±0.11 m/sec, p< 0.05) and was associated with higher levels of valve cusp calcification (Alizarin Red, LA-D +/+ = 10 ± 3% versus LA-D +/- = 20 ± 4%). Reciprocally, overexpression of DDAH1 in hypercholesterolemic littermates reduced ADMA levels (LA-D 0/0 = 1.4 ± 0.2 μmol/L, LA-D Tg/0 = 0.7 ± 0.1μmol/L, p< 0.05) and systolic blood pressure (LA-D 0/0 = 136 ± 6 mmHg, LA-D Tg/0 = 124 ± 4 mmHg, p< 0.05). Interestingly, aortic valve function was not improved by overexpression of DDAH1 (LA-D 0/0 = 2.36 ± 0.06 m/sec versus LA-D Tg/0 mice (2.43 ± 0.21 m/sec), nor was valvular calcification. These results suggest that while endogenous levels of DDAH1 expression protect against increases in circulating ADMA, blood pressure, valvular calcification, and valvular dysfunction. Interestingly, overexpression of DDAH1 does not appear to confer additional protection against progression of valvular stenosis. Collectively, our data suggest effective therapeutic harnessing of the DDAH1/ADMA/NOS axis will require targeting of downstream effector molecules—such as oxidation state of soluble guanylate cyclase—known to be pathologically altered and rate limiting in a variety of cardiovascular diseases.

Heart transplantation is a surgical procedure performed on patients with end-stage heart failure or other irreversible heart disease, Heart transplant prolongs the life of severe heart disease patients. Most of the receipts could survive more than 2-3 years, five-year survival rate could reach 70-80% with immunosuppressive therapy, rejection still an important problem after transplantation. Currently, traditional calcineurin inhibitors, antimetabolite agents, and steroids, wildly used after transplantation, the new generation of immunosuppressive medicines have been developed, and cell-based immunotherapy, as mesenchymal stem cell, myeloid-derived suppressor cells, dendritic cells, pluripotent cells and Treg cells are promising to be used in cellular immunotherapy in organ transplantation.

The cardiology diagnostic are the methods of identifying current or past heart conditions, which can advise caregivers on patient diagnosis and provide a proper therapy plan, nowadays couple new diagnostic methods have been developed and some of them like radionuclide myocardial perfusion imaging, coronary computed tomography angiogram, cardiac magnetic resonance imaging, intravascular ultrasonography, optical coherence tomography, intravascular thermography, intravascular elastography, and near-infrared spectroscopy have been approved for clinical use. Not only the advanced technologies, the new biomarkers, and genetic markers may provide new potential targets for the diagnosis, therapy, and prevention of heart diseases.