CSF1R antagonist / Chroma Therap - LARVOL DELTA

Pharmacodynamic assessment in whole blood for the BET bromodomain inhibitor CPI-0610 of target engagement in patients with progressive lymphoma (AACR 2018) - P1; "CCR2, FN1, CSF1R and THBS1 were identified and validated preclinically but in patient samples were difficult to interpret due to lack of robust regulation or low basal levels of expression. In summary, a BET target gene signature assay using whole blood samples was established and implemented in a Phase I lymphoma study which demonstrated that CPI-0610 regulates direct BET target genes in blood cells in a robust and dose-dependent manner."

Clinical • PK/PD data • Lymphoma

PD-1-based combination immunotherapy reinvigorates CD8+ T cells in metastatic pancreatic cancer patients with improved survival (AACR 2018) - "...Here we described the first testing of GVAX prime given with attenuated listeria monocytogenes expressing mesothelin (CRS-207) boost given with or without nivolumab to block PD-1 signaling and evaluated changes in the TME.Experimental Design: Metastatic pancreatic tumor biopsies were obtained at baseline and after 2 GVAX prime and 1 CRS-207 boost from vaccinated patients...In the myeloid compartment, low CSF1R+ tumor associated macrophages and CD68+ CD163+ and CD163- myeloid frequency in post-immunotherapy tumors were associated with less exhaustion of CD8+ T cells and long OS... This study provides evidence that longitudinal changes in immune cell complexity profiles can be correlated with overall survival. Increases in CD8+ early effectors and decreases in monocytes in baseline versus post-immunotherapy tumors are associated with improved survival. The exhausted CD8+ T cell profile in short OS patients may predict early responders versus nonresp

Clinical • IO biomarker • PD(L)-1 Biomarker • Pancreatic Cancer

WSD1227: A novel, oral bioavailable, brain penetrable and reversible VEGFR inhibitor for the treatment of primary and metastatic brain tumors (AACR 2018) - "...Anti-angiogenesis has been proved to be a good strategy to shrink tumor in many cancer treatments, such as bevacizumab in GBM, NSCLC, mBC, cediranib in OC, etc. However, those clinical validated anti-VEGF agents cannot cross BBB effectively due to either large molecule weight or being substrate of BBB efflux transporters. Herein, using our advanced medicinal chemistry with deep knowledge in CNS area, a BBB penetrable, selective and potent VEGFR2 inhibitor WSD1227 is discovered with biochemical IC50 against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFR IC50 22.9nM, PDGFR IC50 19.4nM, cKit IC50 383nM, FLT3 IC50 555 nM and CSF1R IC50 1062nM...Moreover, predicted human PK properties are very promising to offer sufficient target engagement at a pretty low dose in clinic. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic for the treatment of patients with BM whose primary tumors have already been controlled well.

Colorectal Cancer • Non Small Cell Lung Cancer • Ovarian Cancer

The mutational status of residue Y842 in FLT3 predicts the drug response in acute myeloid leukemia (AACR 2018) - "...Similar to the other type III receptor tyrosine kinases, such as KIT, CSF1R, PDGFRA and PDGFRB, ligand binding to the FLT3 induces dimerization, activation of the receptor and auto-phosphorylation...Gene set enrichment analysis (GESA) demonstrated that the Y-to-F mutation causes suppression of anti-apoptotic genes. Taken together, our data suggest that the activation loop tyrosine residue in FLT3 plays an important role in FLT3 downstream signaling and drug sensitivity."

Acute Myelogenous Leukemia

MPL-5821, a macrophage targeted ESMTM p38 MAPK inhibitor, inhibits the production of TLR agonist induced IL-10 whilst sparing T-cell functionality (AACR 2018) - "...MPL-5821 is an ESMTM p38 MAPK inhibitor which not only inhibits IL-10 but also enhances LPS stimulated IL-12p70 and in contrast to conventional p38 MAPK inhibitors provides enhancement of lymphocyte IFN production.The present studies contrast MPL-5821 with multiple non-targeted agents, including inhibitors of HDAC, JAK, PI3K, MEK and CSF-1R, in human PBMC assays...MPL-5821 potently inhibited the R848 induced IL-10 production as measured by Cytometric Bead Array and in contrast to a conventional p38 MAP inhibitor LY2228820 also enhanced IFN production.We studied MPL-5821 in cell suspensions prepared from human ovarian tumor and ascites...MPL-5821 again showed potent inhibition of TLR agonist induced IL-10 with concomitant enhancement of IFN production. We conclude that application of ESMTM technology to macrophage selective delivery of p38 MAPK inhibitors has the potential to inhibit TLR agonist induction of IL-10, which is implicated in limiting the performance of TLR agonist

Cervical Cancer • Ovarian Cancer

Aberrant expression of CSF1R in melanoma is driven through an endogenous viral promoter and it contributes to malignant growth and BRAF-inhibitor resistance (AACR 2018) - "Co-inhibition of CSF1R and BRAF was also tested and resulted in synergistic blockade of cell growth in vitro and xenograft growth in vivo.The CSF1R inhibitor, PLX3397 is currently in clinical trials for glioblastoma, prostate, breast cancers and other cancers. These data present a preclinical rationale for its study in malignant melanoma."

Breast Cancer • Hodgkin Lymphoma • Melanoma

Dual inhibitor of immunokinase and pan-RAF for the treatment of KRAS-mutated cancers (AACR 2018) - "...As a result, targeting of TAMs may be a promising new approach to cancer treatment.CSF1 is the crucial growth and differentiation factor for macrophage and CSF1R is exclusively expressed by cells of the monocyte lineage, suggesting that CSF1R is an attractive therapeutic target to enable interference with TAMs.In preclinical models, macrophage depletion by CSF-1R inhibitor increased the antitumor effects of VEGF-targeted therapies...SJP-1601 not only improved the efficacy of adoptive T cell therapy through inhibition of immunosuppressive macrophage recruitment and activation in immunocompetent mice but also potentiated the response of xenograft with mutant KRAS by preventing pan-RAF. Our findings suggest that SJP-1601 could be an excellent preclinical candidate for the treatment of cancer with mutant K-RAS."

IO Biomarker • Colorectal Cancer

Comparative genomic analysis of young-onset and late-onset colorectal cancer (AACR 2018) - "...DOT1L (9.82% vs. 1.95%, P=0.0014), IGF1R (6.12% vs. 1.72%, P=0.0057), BRCA1 (5.61% vs. 1.47%, P=0.0069), JUN (6.25% vs. 1.17%, P=0.0104), PTCH1 (7.14% vs. 2.7%, P=0.0151), TSHR (5.36% vs. 1.17%, P=0.0253), EIF1AX (3.06% vs. 0%, P=0.02811), JAK2 (2.0% vs. 0.46%, P=0.0311), EP300 (8.67% vs. 4.41%, P=0.0414), PHOX2B (2.20% vs. 0.27%, P=0.0419), SMC1A (3.57% vs. 0%, P=0.0446) and CSF1R (3.02% vs. 1.03%, P=0.0439) had a significantly higher mutation rate in the young-onset primary CRCs... Mutation rates were found significantly higher in many genes among young-onset primary CRCs compared to late-onset primary CRCs."

BRCA Biomarker • Colorectal Cancer

NMS-P088, a FLT3-KIT-CSF-1R inhibitor with activity on FLT3 F691L as a novel agent in AML (AACR 2018) - "...Several FLT3 inhibitors, including quizartinib, crenolanib and gilteritinib, are currently in advanced clinical testing. Moreover midostaurin, a multikinase inhibitor with activity on FLT3, has been recently approved in FLT3 mut AML in combination with standard chemotherapy...In the disseminated MOLM-13 AML model, repeated oral administration of NMS-P088 as single agent was able to significantly increase survival time, and showed synergy with cytarabine...GLP toxicity studies revealed good tolerability at efficacious exposures, with no cardiac effects and excellent BBB penetration. Thus NMS-P088, a potent FLT3 inhibitor with activity on the gatekeeper mutation, is a preclinical candidate with potential to address an unmet medical need in AML, both as single agent and in combination, as well as for testing in different solid tumors sensitive to immunomodulation."

IO Biomarker • Acute Myelogenous Leukemia • Solid Tumor

CG806, a first-in-class pan-FLT3/pan-BTK inhibitor, demonstrates superiority to other FLT3 and BTK inhibitors against primary patient samples (AACR 2018) - "For AML samples, mutational status of ITD and TKD in FLT3 were assessed by a PCR assay for ITD and by whole exome sequencing for TKD. CG806 has more potent activity against a broader subset of AML samples relative to other FLT3 inhibitors, including midostaurin, gilteritinib, quizartinib, sorafenib, crenolanib, and dovitinib. CG806 is a potent and broadly active FLT3 inhibitor in AML and BTK inhibitor in CLL. These data reveal CG806s enhanced activity relative to kinase inhibitors currently approved for each indication and support further clinical development of CG806 for both AML and CLL."

Clinical • Head-to-Head • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Indolent Lymphoma

Identification of novel and known hotspot variants in African Americans with colorectal cancer (AACR 2018) - "...Lastly, the 9 genes without variants in our population are CDKN2A, SMARCB1, AKT1, ALK, FGFR2, IDH2, CSF1R, HNF1A and MPL. We have identified novel and known hotspot somatic variants in African Americans with colorectal lesions. We have identified novel and known hotspot somatic variants in African Americans with colorectal lesions. Patients with significant hotspot variants, primarily missense alterations, had a worse prognosis. As a result, cancer gene panel hotspot profile should be taken into consideration when treating African American CRC patients."

Colorectal Cancer

Role of Neuropilin 2 in orchestrating the functions of osteoclasts in promoting prostate cancer bone metastasis (AACR 2018) - "We hypothesize that PCa-induced NRP2 expression in OC is necessary for low osteolytic activity and thus favors an osteoblastic lesion in PCa bone metastasis. Mouse OC precursors were isolated from bone marrow of C57BL/6 mice as well as transgenic CSF1R-cre; NRP2 Flox/Flox inducible mice where addition of 4-hydroxytamoxifen depletes NRP2 specifically from the myeloid cells. We will also address how PC3 CM-induced OCs escapes the inhibition of NRP2. Together, this approach will elucidate the role of NRP2 axis on OCs in promoting PCa-induced bone metastasis and will aid in determining whether NRP2 axis can be a therapeutic target."

Prostate Cancer

Localized synchrotron radiation in mice induces persistent systemic genotoxic events mediated by the functional immune system (AACR 2018) - "...The MRT irradiations was repeated in immune-deficient mice: NSG, CCL2 knock-outs, and in C57BL/6 mice treated with anti-CSF1R antibody which effectively depletes macrophages...1. Ventura et al, Cancer Research, e-pub (2017)."

Preclinical • Oncology

Comprehensive profiling the immune-status of a broad range of in vivo syngeneic models (AACR 2018) - "...Furthermore, not only population of immune cells but also the expressions of immune related gene were analyzed by RE-PCR which are the genes related regulatory of T cells i.e., CD4, Foxp3, GITR; gene of tumor associated macrophage CSF1R, CD68, CX3CR1, ITGAM, CD163, MARC1; gene of co-stimulator receptors of T cells ICOS, CD137(Tnfrsf9), OX40(Tnfrsf4); co-inhibitory receptors of T cell BTLA, HAVCR2, CTLA4, LAG3, CD28, PDCD1; and gene of co-inhibitory ligands of tumor cells CD274, CD137L(Tnfsf9), PDCD1LG2, HVEM(Tnfsf14), OX40L(Tnfsf4)...We believe that this profiling data will help many scientists to properly select correct model to support R&D and to better understand how immune therapeutically agent acts in the immune system. With this comprehensive research data, were now at a point where this information has started to become translated into treatment possibilities for cancer patients."

IO Biomarker • PD(L)-1 Biomarker • Preclinical • Oncology

Genotype-fitness maps guide targeted therapy combination in lung adenocarcinoma (AACR 2018) - "...Our screen covered 17,255 ORFs (open reading frame constructs) representing 12,728 wildtype and mutated genes, and examined the effects of a first-generation EGFR inhibitor (erlotinib), a third-generation EGFR inhibitor (osimertinib) and a MEK inhibitor (binimetinib) on evolutionary selection, alone or in combination...Novel resistance mechanisms include alternative tyrosine kinases (NTRK, PDGFRB, CSF1R, KIT), KRAS, G-coupled protein receptors, transcription factors (SOX15, FOXA1), and cellular transporters (ABCG2)...The orthogonal resistance landscapes of EGFR inhibition and MEK inhibition translate into highly synergistic effects in drug combination, with effective prediction of combinatorial fitness from the single-agent fitness landscapes using generalized linear models. These results validate this approach as a systematic method to address the combinatorial problem of optimizing drug combinations and doses to directly anticipate and address cancer evolution."

Non Small Cell Lung Cancer

CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib (AACR 2018) - "CBT-102 is an oral mTKI inhibiting several key oncogenic drivers including angiogenesis via VEGFR and PDGFR, MAPK pathway via B-RAF and C-RAF, in addition to inhibiting RET, CSF1R, c-KIT, and FLT3. CBT-102 demonstrated improved efficacy in HCC xenografts models compared to sorafenib and does not appear to have the cardiac liability observed with sorafenib. CBT-102 will advance into GLP toxicology studies with a potential IND filing in 2H 2018."

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

CSF1R-RELATED LEUKOENCEPHALOPATHY (ADPD 2017) - "Although brain biopsy was previously needed for the diagnosis of CSF1R-related leukoencephalopathy, the diagnosis can now be established by commercial genetic testing. However, there is no cure for CSF1R-related leukoencephalopathy and palliative therapies are limited."

Clinical • Alzheimer's Disease • Biosimilar • CNS Disorders • Epilepsy • Gene Therapies • Parkinson's Disease