P2, N=119, Completed, Astellas Pharma Europe B.V. | Phase classification: P2a --> P2

In summary, our study elucidates that metformin inhibits sympathetic neuronal differentiation in PC12 cells by disrupting TrkA/ERK/EGR1 and p35/CDK5 signaling. This research contributes to uncovering a novel signaling mechanism in drug response during sympathetic neuronal differentiation, enhancing our understanding of the intricate molecular processes governing this critical aspect of neurodevelopment.

P2, N=9, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Mar 2024 --> Sep 2024

Tanezumab 20 mg met the primary efficacy endpoint at week 8. Conclusions on longer-term efficacy are limited since the study was not designed to evaluate the durability of the effect beyond 8 weeks. Safety findings were consistent with adverse events expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. Clinicaltrials.gov identifier: NCT02609828.

In vivo tumorigenesis experiments, Tanezumab markedly alleviated nerve invasion of PC cells as well as relieved nociceptive conduction in animal models. These findings displayed that NGF/TrkA encouraged the neuroinvasive potential of PC cells by activating the Warburg effect in DRG cells through upregulation of TDE-miR-21-5p expression.

These results suggest that MDZ may inhibit PDAC-induced transdifferentiation into sympathetic nerves.

Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing "pain" as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

Interestingly, proliferation was significantly higher in NGF-treated cells than in control cells, and this effect was completely reversed by the YAP small molecule inhibitor-verteporfin...Taken together, these data provide the first direct evidence of crosstalk between the NGF signaling and Hippo cancer pathways, an interaction that affects cervical cancer progression. Our study indicates that combined targeting of the NGF signaling and the Hippo pathway represents a novel therapeutic strategy for treatment of cervical cancer.

Transfected cell lines or patient-derived organoids (PDO) were treated with 5-fluorouracil (5-FU) and 6-mercaptopurine (6-MP) and drug response was correlated with ADSL expression levels. Our results suggest that ADSL is a novel oncogene in CRC, modulating mitochondrial function, metabolism and oxidative stress, thus promoting cell cycle progression, proliferation and migration. Our results also suggest that ADSL is a predictive biomarker of response to 6-mercaptopurine in the pre-clinical setting.

The primary drug that causes hematotoxicity in ALL children is 6-mercaptopurine (6-MP)...We also found no association between TPMT genotypes and TPMT phenotypes. The 6-MeMP/6-TGN ratio is associated with hematotoxicity in ALL children during maintenance therapy but is not strong enough to predict hematotoxicity.

All children received 6-mercaptopurine and cis-retinoic acid, and four had azacytidine...Busulfan, cyclophosphamide, and melphalan in three children with matched sibling donors and treosulfan, thiotepa, and fludarabine in the three children with alternate donors resulted in a stable graft... The main factors determining optimal outcomes in HSCT for JMML include adequate disease control before HSCT and a myeloablative conditioning regimen. Graft rejection remains the most significant barrier to cure. Risk stratification based on molecular diagnosis helps avoid HSCT in children with CBL gene mutation

The patient failed multiple lines of treatment (dasatinib, nilotinib, hydroxyurea, cytarabine subcutaneous, 6-mercaptopurine and interferon) and progressed to the blast phase a few months later. CONCLUSIONS We report an unusual case of CML, presented with significant dysgranulopoiesis with an aggressive clinical course including SM uncovered during the disease course with subsequent transformation to the blast phase. The different biological behavior of this case underscores the need for studies on a larger number of cases to explore the significance of the aforementioned coexistent features.

With this diagnosis, chemotherapy continued with all-trans retinoic acid (ATRA ), methotrexate and mercaptopurine, going into remission three months after the start of treatment, with no need for bone marrow transplantation...The treatment is divided into 3 phases: Induction, which aims to reduce the number of leukemic cells, the most suitable drug being trans-retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy with anthracycline or anthracycline chemotherapy more ACT... Early diagnosis and treatment are essential for the successful treatment of AML subtype M3, in addition to preventing future ischemic events, which are influenced by increased blood viscosity due to the presence of blasts in peripheral blood.

No previous ALL-specific treatment, with the exception of corticosteroids and/or single dose vincristine and/or up to 3 doses of cyclophosphamide (cycloph.) plus standard prephase treatment are allowed. The 1st induction cycle consists of inotuzumab ozogamicin (InO) 0.8 mg/m2 on day1 and 0.5 mg/m2 on days 8 and 15 together with dexamethasone 10 mg/m2 (days 7-8, days 14-17) and 1 intrathecal injection of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dexa)...Patients achieving a complete remission are offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/AraC/cycloph./Dexa) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-mercaptopurine/MTX... Replacement of conventional induction chemotherapy by InO is feasible, results in promising remission rates, and may reduce the risk of early morbidity and lethality, particular in older patients with acute B lymphoblastic leukemia.

The overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit.

Methods A drug sensitivity profiling, comprising 7 standard chemotherapeutic agents (6-mercaptopurine, cytarabine, daunorubicin, vincristine, methotrexate, prednisone, dexamethasone), was performed on 4 CD9+ (697, BV-173, RS4;11, SUP-B15) and 3 CD9- (Reh, SEM, KOPN-8) B-ALL cell lines...Conclusions Our results indicate that CD9 negativity was definitively linked to glucocorticoid resistance, which could be reversed by CD9 reactivation through a receptor-independent mechanism. Comprehensive understanding of the interaction between CD9 and glucocorticoid susceptibility could lead to improved therapeutic strategies for resistant pediatric B-ALL.

In addition to its chemosensitizing effects, CCI52 and CCI52-14 inhibited the growth of MYCN-amplified high-risk neuroblastoma cell lines and delayed tumor progression in a MYCN-driven, transgenic mouse model of neuroblastoma. These multifunctional inhibitors may be useful for the further development of anticancer agents and as tools to better understand 6-MP metabolism.

Findings of this study may provide basic knowledge for personalized medicine for thiopurine treatment in pediatric acute lymphoblastic leukemia patients.

Expression of mutant NT5C2 mutations also significantly reduced thiopurine uptake in vitro with concomitant increase in efflux of 6-mercaptopurine (MP) metabolites, plausibly via indirect effects on drug transporter pathways...Collectively, our data indicated that NT5C2 mutations alter thiopurine metabolism and cellular disposition, but also influenced endogenous nucleotide homeostasis and thiopurine-induced metabolomic response. These complex mechanisms contributed to NT5C2-mediated drug resistance in ALL and pointed to potential opportunities for therapeutic targeting in relapsed ALL.

In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3-4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15*3 allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

PRPS1 wild type (WT) showed different resistance to 6-mercaptopurine (6-mp) in different metabolic cells because it could be inhibited by adenosine diphosphate or guanosine diphosphate negative feedback...The interim analysis of the Treatment Regimen for Children or Adolescent with mature B cell non-Hodgkin's lymphoma in China (CCCG-B-NHL-2015 study) confirms the value of high-dose methotrexate (MTX) and cytarabine (ARA-C) in high-risk paediatric patients with BL. However, there remains a subgroup of patients with lactate dehydrogenase higher than four times of the normal value (4N) for whom novel treatments are needed. Notably, we found that the combination of thiopurines and the phosphoribosylglycinamide formyltransferase (GART) inhibitor lometrexol could serve as a therapeutic strategy to overcome thiopurine resistance in BL.

Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8...LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose)... AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Research Funding: U.S. National Institutes of Health, Other Foundation, Pharmaceutical/Biotech Company

Successful treatment requires initial high-intensity chemotherapy, followed by low-intensity oral maintenance therapy with oral 6-mercaptopurine (6MP) and methotrexate (MTX) until 2-3 years after disease onset. Using the new cross-validated mathematical model, simulations of different treatment protocols showed a linear dose-effect relationship and reduced ANC variability for constant dosages. Advanced modeling allows the identification of optimized control criteria and the weighting of specific influencing factors for protocol design and individually adapted therapy to exploit the optimal effect of maintenance therapy on survival.

Finally, we found that knockdown of AOC1 inhibited the epithelial-mesenchymal transition (EMT) in human gastric cancer by increasing the expression of epithelial markers E-cadherin, as well as decreasing mesenchymal marker N-cadherin, SNAIL and Slug. Our study suggests that AOC1 functions as an oncogene in human gastric cancer by activating the AKT signaling pathway and EMT process and maybe a target of 6-mercaptopurine, which provides new insight in the clinical use of AOC1 in gastric cancer therapy.

Completed --> Active, not recruiting

Our findings support the idea that predetermination of genotypes and monitoring of thiopurine metabolism for Chinese pediatric patients afflicted by ALL is necessary to effectively predict the efficacy of treatments and to minimize the adverse effects of 6-MP maintenance therapy.

In vivo, treatment with OV alone or in combination with CDDP significantly reduced the tumor sphere-forming ability and decreased EV cargos containing mTOR, PI3K, STAT3, β-catenin, and miR-21-5p. In summary, our findings provide further strong evidence of OV's therapeutic effect in OSCC.