This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human glioblastoma avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for glioblastoma.

These findings show that peripheral respiratory viral infection with IAV is capable of altering OL homeostasis and indicate that microglia activation is likely involved in the process.

MCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.

P1b/2, N=405, Terminated, Pfizer | Active, not recruiting --> Terminated; The study was terminated since there was no need for further safety or efficacy data to be collected. The participants having benefit from the Investigational treatments have been moved to a continuation study (NCT05059522)

P1, N=64, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2022 --> Feb 2023 | Trial primary completion date: Oct 2022 --> Feb 2023

In a chick chorioallantoic membrane (CAM) tumor model implanted with Hep3B cells, tumor growth and tumor-induced angiogenesis were significantly blocked by compound 3 to a similar extent as pexidartinib (1). Overall, compound 3, a bioisostere of pexidartinib, is an effective dual inhibitor to block CSF1R kinase and CSF1 production, resulting in significant inhibition of tumor growth.

Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients.

Thus, we demonstrated that the anticancer effects of masitinib are not due to its targeting c-kit, but rather to its targeting the redox balance via the JNK pathway in HepG2 cells. These results suggest that masitinib has the potential to provide a robust antitumor effect in tumor lesions and could also be applied to a broad range of other anticancer therapies.

Inhibition of CSF1 receptor partly suppressed the paracrine effects of HPCs on HUVECs. Taken together, our study indicates that inhibition of the paracrine function of HPCs through modulation of their differentiation status and inhibition of CSF1 signaling is a promising strategy for inhibition of angiogenesis during pathological progression.

Patients with TGCT not amenable to surgery were treated in 2 cohorts: A (no prior anti-CSF1/CSF1R therapy except imatinib and/or nilotinib) and B (prior anti-CSF1/CSF1R therapy). At the RP2D of vimseltinib, patients in both cohorts reported improvement in worst and average pain and joint swelling and stiffness at Week 25. Results support continued evaluation of vimseltinib at this dose level in the ongoing phase 3 MOTION trial (NCT05059262).

P1b/2, N=398, Active, not recruiting, Pfizer | Trial completion date: Apr 2022 --> Feb 2023 | Trial primary completion date: Apr 2022 --> Feb 2023

P1, N=64, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2022 --> Oct 2022 | Trial primary completion date: Jun 2022 --> Oct 2022

A population-based cohort study of EC patients further demonstrated that the use of haloperidol was associated with increased EC-specific mortality. Collectively, these findings indicate that clinical use of haloperidol could potentially be harmful to female patients with EC.

We investigated in depth the mechanism of β-Klotho regulating CSF-1 secretion and found that β-Klotho inhibits the phosphorylation of p65, which blocked the nuclear translocation of p65, thereby inhibiting the secretion of CSF-1 by EC cells. The above results indicate that β-Klotho-mediated inhibition of CSF-1 secretion reduces the migration of macrophages to tumor tissue and delays the progression of EC.

P1b/2, N=82, Terminated, Pfizer | Completed --> Terminated; Study was halted prematurely due to insufficient efficacy. Not due to safety reasons.

Keeping the knee in 90° of flexion provides the furthest distance from the saphenous vein on the medial side, the peroneal nerve on the lateral side, and the popliteal artery near the posterior septum when making the posterior portals.Transillumination of the posterior portals is recommended.Perforation of the septum should be in the posterolateral to posteromedial direction, allowing surgeons to have a wider "safe zone" to decrease the chance of vascular injury to the popliteal artery. CSF = colony-stimulating factorMCL = medial collateral ligamentMRI = magnetic resonance imagingPL = posterolateralPM = posteromedialPA = popliteal arteryROM = range of motionTS = trans-septalIKDC = International Knee Documentation Committee.

This review concludes the roles of biological mediators of TME interact with TAMs in BRCA that provide a rationale for TAM-targeted therapy as a novel treatment approach for BRCA.

High expression of HIST1H1E was resistant to trametinib, selumetinib, RDEA119, docetaxel and 17-AAG, High expression of UBE2C was resistant to masitinib, and Low expression of ERO1B made the EC more sensitive to FK866. We constructed an EC risk score model composed of 8 DEGs and gene resistance analysis, which can provide reference for prognosis prediction, diagnosis and treatment of the EC patients.

Given the polymorphic nature of the enzymes involved, future studies are needed to determine the impact of CYP genetic polymorphisms on masitinib metabolism. This information could ultimately provide evidence to inform precision prescribing for masitinib to ensure safety and efficacy for future patients.

VL51 developed resistance to idelalisib, copanlisib, duvelisib, and umbralisib...The use of the IL-6R blocking antibody tocilizumab, the STAT3 inhibitor stattic, the LIN28 inhibitor LIN1632, the PDGFR inhibitor masitinib and the anti-CD19 antibody drug conjugate loncastuximab tesirine were active compounds in the resistant cells as single agents and/or in combination with PI3K//inhibition. Findings were validated on additional in vitro lymphoma models and on clinical specimens. A novel model of resistance obtained from splenic MZL allowed the identification of therapeutic approaches able to improve the anti-tumor activity of PI3Kttinhibitors in B-cell lymphoid tumors.

The PFH@LSLP was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O-saturated PFH core could alleviate the tumor hypoxia by O supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8 T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.

Masitinib exposure increased apoptosis, while the cell counts and cell viability decreased in a dose- and application interval-dependent manner, with increased impact in the 12-h double-dose regimen. These in vitro effects of masitinib in canine prostate cancer and associated metastasis support further in vivo research and modifications of the clinical treatment protocol in future studies.

Finally, potential therapeutic drugs, such as masitinib, were obtained by the cMap database. miR-1 may play a vital part in NPC tumorigenesis and progression by regulating focal adhesion kinase to participate in cell mitosis, regulating ECM degradation, and affecting the PI3K/Akt signaling pathway. miR-1 has the potential to be a therapeutic target for NPC.

We propose combination therapy of masitinib and cromolyn may represent an innovative treatment in neurodegenerative diseases. Combination therapy may be more advantageous that it enables combined application of lower doses of both drugs, providing less side effects.

P1, N=64, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=220 --> 64 | Trial completion date: Jan 2022 --> Jun 2022 | Trial primary completion date: Jan 2022 --> Jun 2022

Tumours coopt intratumoural HSPC fate determination via CSF-1 signaling to overcome the effects of RT. Thus, limiting intratumoural HSPC activity represents an attractive strategy for improving the clinical treatment of solid tumours.

In summary, we showed that CSF-1R blockade with the SMI GW2580 can reprogram GAM phenotype and thereby improve T cell activation. This strongly suggests further studies on the use of GW2580 in combination with immunotherapeutic approaches for the treatment of GBM.

Further validation of this bifunctional form will be presented. Conclusions Our findings provide a potential strategy for simultaneously targeting TAM and exhausted T cells to potentiate anti-tumor immunity for treatment of triple-negative breast cancer.

P1b/2, N=398, Active, not recruiting, Pfizer | Trial completion date: Feb 2024 --> Apr 2022 | Trial primary completion date: Feb 2024 --> Apr 2022

GW2580, a CSF1-receptor inhibitor was tested in-vitro as well as in-vivo, singularly and in combination with S-nitrosoglutathione (GSNO), an active NO donor. In-vivo dosage of 40mg/kg/day for GW2580 and 10mg/kg/day for GSNO were used... Our findings demonstrated a direct role of increased NO-based immunotherapy to augment the action of CSF1R inhibition to suppress the macrophage polarization in in-vivo models for castration resistant prostate cancer.

P1b/2, N=392, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=620 --> 392

We conclude that RNAscope CSF1 CISH may be a valuable adjunct for the diagnosis of TGCT of all types, especially those with atypical or malignant morphologic features. Detection of CSF1 mRNA expression may also have predictive significance in cases where use of the CSF1 inhibitor pexidartinib is considered.

In particular, cabozantinib when used in combination trials and ipatasertib, when used with abiraterone in patients who harbor phosphatase and tensin homologue (PTEN) loss, have been promising...However, multiple drugs have failed primary endpoints in prostate cancer. Therefore, further understanding of the potential mechanisms of resistance, combination and trial design of combination therapy may help pave the way for targeting kinase inhibition in prostate cancer.

Furthermore, PD1 or PD-L1 inhibitors might be effective in more aggressive PTCL, including PTCL-NOS and AITL. In summary, we show the clinical characteristics, survival progno- sis, oncogenesis signaling pathways, and newly identified molecular markers of PTCL, in addition to provide evidence for clinical trials of novel agents and to allow better therapeutic opportunities for PTCL.

This allows for the uncovering of meaningful TME-induced immune evasion mechanisms and immune suppressive cytokine-related effects. Further immune reconstitution in this melanoma model may provide a novel in vitro tool for preclinical testing of immune modulatory agents.

In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.

Nature Biotechnology. March 2020.