Stefan Hart - Academia.edu (original) (raw)
Papers by Stefan Hart
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectiv... more Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collageninduced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers. ■ INTRODUCTION An estimated 1% of the world’s population is afflicted by rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder leading to the destruction of articular cartilage and ankylosis of the joints. RA is a disabling and painful condition, which leads to substantial loss of functioning and mobility if no...
Cannabinoids, the active components of marijuana and their endogenous counterparts were reported ... more Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite. Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells. Here, we demonstrate that anandamide, � 9-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity. EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signalin...
La presente invention concerne des polypeptides de kinase mutants et des variants de kinase chois... more La presente invention concerne des polypeptides de kinase mutants et des variants de kinase choisis dans le groupe comprenant : AATYK (AATK), ABL1, ACK1, ALK, ARG, AXL, BMX, BRK, BTK, CCK4, CSFR1, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, FAK, FER, FES, FGFR1, FGFR2, FGFR4, FLT3, FRK, FYN, HER2, HER3, HER4, IGF1R, INSR, ITK, JAK1, JAK2, JAK3, LCK, LMTK2 (AATYK2/BREK), LYN, MATK, MER, MET, NTRK1, NTRK2, NTRK3, PDGRFA, PDGFRB, PTK-9, PYK2, RET, RON, ROR1, ROR2, ROS, RYK, STYK, SYK, TEC, TEK, TIE, TNK1, TXK, TYK2, TYRO3, VEGFR1, VEGFR2, VEGFR3, YES1, et ZAP70, des sequences nucleotidiques codant pour des polypeptides de kinase mutants et des variants de kinase, ainsi que differents produits et procedes utiles pour le diagnostic et le traitement de differentes maladies et de differents etats pathologiques lie(e)s a la kinase, comprenant le criblage et l'identification de nouveaux modulateurs de proteine kinase.
Blood, 2009
1888 Poster Board I-911 Introduction: Abnormalities in JAK2 and FLT3 kinases are reported in vari... more 1888 Poster Board I-911 Introduction: Abnormalities in JAK2 and FLT3 kinases are reported in various hematological malignancies and may underlie the pathogenesis of these diseases. An activating mutation of JAK2, namely JAK2V617F is the most common mutation in bcr-abl-negative chronic myeloproliferative disorders (MPDs). Activation of wild type JAK2 has been reported in Hodgkin lymphoma (HL) and primary mediastinal large cell Non-Hodgkin lymphomas (NHL) due to loss of Suppressor of Cytokine Signaling (SOCS)-1 gene. Abnormalities in FLT3 are present in ∼30% of acute myelogenous leukemias (AML). SB1518 is a potent inhibitor of both JAK2 (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) as well as FLT3 (IC50 = 22 nM) and it mutant D835Y (IC50 = 6 nM). As a consequence, SB1518 inhibits the proliferation of human leukemia and lymphoma cell lines dependent on either JAK2 or FLT3 activation (IC50 =35–240 nM), and has antitumor activity in nude mouse models of FLT3- (MV4-11) or JAK2-de...
Journal of Clinical Oncology, 2005
6624 Background: Combination therapy is often not an option for multiple relapsed/refractory Hodg... more 6624 Background: Combination therapy is often not an option for multiple relapsed/refractory Hodgkin’s disease patients particularly after salvage high-dose chemotherapy and transplant. Vincristine is a cell cycle-specific anticancer drug, with established activity in Hodgkin’s disease. Sphingosomal vincristine (SV) is a novel sphingosome encapsulated formulation of vincristine, which presents several advantages over regular vincristine. SV has a longer half-life (15 hours versus 15 minutes), can be given uncapped, and shows accumulation in tumor sites in experimental models, providing a rationale for this cell-cycle specific agent. Methods: : SV was evaluated as a single agent for the treatment of patients with relapsed or refractory Hodgkin’s disease including those who failed auto or allogeneic transplantation. SV was administered at 2 mg/m2 (no dose capping) IV over 1 hour every 14 days. Patients were restaged every two cycles, responders continued two cycles beyond their best response to a maximum of...
Molecular Cancer Therapeutics, 2010
![Research paper thumbnail of Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lym...](https://attachments.academia-assets.com/87170031/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 2011
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase crit... more Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC 50 = 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) and FLT3 (IC 50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC 50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
Journal of Clinical Oncology, 2012
Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway... more Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. Patients and Methods Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. Results Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area...
Leukemia, 2011
SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selec... more SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC 50 ¼ 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) within the JAK family (IC 50 ¼ 1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC 50 ¼ 22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2 V617F-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/ STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2 V617F patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.
e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to ... more e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to target key signaling pathways in many different cancers. In general, broad-spectrum kinase inhibitor...
Blood
Currently, most multiple myeloma (MM) patients experience relapse and develop resistance to stand... more Currently, most multiple myeloma (MM) patients experience relapse and develop resistance to standard treatments. A recent study showed that patients who relapsed had poor outcomes, with an overall survival of only 6 months and an event-free survival of 1 month. The PI3K/mTOR/AKT pathway represents a critical target in MM because it stimulates proliferation, survival, and drug resistance of MM cells. VS-5584 is a novel agent, with specific and equipotent activity against mTOR and all 4 Class I PI3K isoforms, without relevant activity on 400 other lipid and protein kinases. Here we report that VS-5584 is highly efficacious against a wide panel of MM cells including Velcade- and Doxorubucin- resistant cell lines. This efficacy is maintained even in the presence of additional MM growth factors, IL-6 and IGF-1, and seems independent of PTEN status in the cell lines. Importantly, VS-5584 shows similar efficacy in patient myeloma cells and preferential tumor cell targeting compared to heal...
Blood
2913 Poster Board II-889 Introduction: Polycythemia vera (PV) is a myeloproliferative neoplasm (M... more 2913 Poster Board II-889 Introduction: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) in which the patients' erythroblastic lineage acquires a hyper-proliferative potential but retains normal maturation, leading to elevated hematocrit and its attendant risks. The discovery of an activating mutation (JAK2V617F) in almost all PV patients and about half of the other Ph-negative MPNs prompted the development of small-molecule JAK2 inhibitors as novel therapeutics. In preclinical translational studies, these compounds have been tested against primary hematopoietic cells in ex vivo assays such as the endogenous erythroid colony (EEC) assay or proliferation assay with erythroid progenitors (EP). Results have been mixed, with some compounds showing selective activity against JAK2V617F-bearing cells while…
Oncotarget, Jan 24, 2017
The PI3K/mTOR/AKT pathway is an integral regulator of survival and drug resistance in multiple my... more The PI3K/mTOR/AKT pathway is an integral regulator of survival and drug resistance in multiple myeloma (MM). VS-5584 was synthesized with dual-specific and equipotent activity against mTORC1/2 and all four Class I PI3K isoforms so as to durably inhibit this pathway. We show that VS-5584 is highly efficacious against MM cell lines even in the presence of IL-6 and IGF-1 and that this growth inhibition is partially dependent on Bim. Importantly, VS-5584 triggers apoptosis in patient cells with a favorable therapeutic index. Gene expression profiling revealed a VS-5584-induced upregulation of RARRES3, a class II tumor suppressor gene. MM patient databases, UAMS and APEX, show that RARRES3 is under-expressed in 11q13 subsets which correlates with the reduced effectiveness of VS-5584 in 11q13 cell lines. Silencing RARRES3 expression significantly rescues VS-5584-induced cell death and increases cyclin D2 expression but not cyclin D1 or other cyclins implying a role for RARRES3 in cell cyc...
European Journal of Cancer Supplements
Molecular Cancer Therapeutics, Nov 1, 2007
In a variety of established tumour cell lines, but also in primary mammary epithelial cells metal... more In a variety of established tumour cell lines, but also in primary mammary epithelial cells metalloprotease-dependent transactivation of the EGFR, and EGFR characteristic downstream signalling events were observed in response to stimulation with physiological concentrations of GPCR agonists such as the mitogens LPA and S1P as well as therapeutically relevant concentrations of cannabinoids. Moreover, this study reveals ADAM17 and HB-EGF as the main effectors of this mechanism in most of the cancer cell lines investigated. However, depending on the cellular context and GPCR agonist, various different members of the ADAM family are selectively recruited for specific ectodomain shedding of proAR and/or proHB-EGF and subsequent EGFR activation. Furthermore, biological responses induced by LPA or S1P such as migration in breast cancer and HNSCC cells, depend on ADAM17 and proHB-EGF/proAR function, respectively, suggesting that highly abundant GPCR ligands may play a role in tumour develop...
European Journal of Cancer Supplements, 2010
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectiv... more Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collageninduced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers. ■ INTRODUCTION An estimated 1% of the world’s population is afflicted by rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder leading to the destruction of articular cartilage and ankylosis of the joints. RA is a disabling and painful condition, which leads to substantial loss of functioning and mobility if no...
Cannabinoids, the active components of marijuana and their endogenous counterparts were reported ... more Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite. Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells. Here, we demonstrate that anandamide, � 9-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity. EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signalin...
La presente invention concerne des polypeptides de kinase mutants et des variants de kinase chois... more La presente invention concerne des polypeptides de kinase mutants et des variants de kinase choisis dans le groupe comprenant : AATYK (AATK), ABL1, ACK1, ALK, ARG, AXL, BMX, BRK, BTK, CCK4, CSFR1, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, FAK, FER, FES, FGFR1, FGFR2, FGFR4, FLT3, FRK, FYN, HER2, HER3, HER4, IGF1R, INSR, ITK, JAK1, JAK2, JAK3, LCK, LMTK2 (AATYK2/BREK), LYN, MATK, MER, MET, NTRK1, NTRK2, NTRK3, PDGRFA, PDGFRB, PTK-9, PYK2, RET, RON, ROR1, ROR2, ROS, RYK, STYK, SYK, TEC, TEK, TIE, TNK1, TXK, TYK2, TYRO3, VEGFR1, VEGFR2, VEGFR3, YES1, et ZAP70, des sequences nucleotidiques codant pour des polypeptides de kinase mutants et des variants de kinase, ainsi que differents produits et procedes utiles pour le diagnostic et le traitement de differentes maladies et de differents etats pathologiques lie(e)s a la kinase, comprenant le criblage et l'identification de nouveaux modulateurs de proteine kinase.
Blood, 2009
1888 Poster Board I-911 Introduction: Abnormalities in JAK2 and FLT3 kinases are reported in vari... more 1888 Poster Board I-911 Introduction: Abnormalities in JAK2 and FLT3 kinases are reported in various hematological malignancies and may underlie the pathogenesis of these diseases. An activating mutation of JAK2, namely JAK2V617F is the most common mutation in bcr-abl-negative chronic myeloproliferative disorders (MPDs). Activation of wild type JAK2 has been reported in Hodgkin lymphoma (HL) and primary mediastinal large cell Non-Hodgkin lymphomas (NHL) due to loss of Suppressor of Cytokine Signaling (SOCS)-1 gene. Abnormalities in FLT3 are present in ∼30% of acute myelogenous leukemias (AML). SB1518 is a potent inhibitor of both JAK2 (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) as well as FLT3 (IC50 = 22 nM) and it mutant D835Y (IC50 = 6 nM). As a consequence, SB1518 inhibits the proliferation of human leukemia and lymphoma cell lines dependent on either JAK2 or FLT3 activation (IC50 =35–240 nM), and has antitumor activity in nude mouse models of FLT3- (MV4-11) or JAK2-de...
Journal of Clinical Oncology, 2005
6624 Background: Combination therapy is often not an option for multiple relapsed/refractory Hodg... more 6624 Background: Combination therapy is often not an option for multiple relapsed/refractory Hodgkin’s disease patients particularly after salvage high-dose chemotherapy and transplant. Vincristine is a cell cycle-specific anticancer drug, with established activity in Hodgkin’s disease. Sphingosomal vincristine (SV) is a novel sphingosome encapsulated formulation of vincristine, which presents several advantages over regular vincristine. SV has a longer half-life (15 hours versus 15 minutes), can be given uncapped, and shows accumulation in tumor sites in experimental models, providing a rationale for this cell-cycle specific agent. Methods: : SV was evaluated as a single agent for the treatment of patients with relapsed or refractory Hodgkin’s disease including those who failed auto or allogeneic transplantation. SV was administered at 2 mg/m2 (no dose capping) IV over 1 hour every 14 days. Patients were restaged every two cycles, responders continued two cycles beyond their best response to a maximum of...
Molecular Cancer Therapeutics, 2010
Journal of Medicinal Chemistry, 2011
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase crit... more Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC 50 = 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) and FLT3 (IC 50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC 50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
Journal of Clinical Oncology, 2012
Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway... more Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. Patients and Methods Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. Results Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area...
Leukemia, 2011
SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selec... more SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC 50 ¼ 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) within the JAK family (IC 50 ¼ 1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC 50 ¼ 22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2 V617F-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/ STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2 V617F patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.
e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to ... more e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to target key signaling pathways in many different cancers. In general, broad-spectrum kinase inhibitor...
Blood
Currently, most multiple myeloma (MM) patients experience relapse and develop resistance to stand... more Currently, most multiple myeloma (MM) patients experience relapse and develop resistance to standard treatments. A recent study showed that patients who relapsed had poor outcomes, with an overall survival of only 6 months and an event-free survival of 1 month. The PI3K/mTOR/AKT pathway represents a critical target in MM because it stimulates proliferation, survival, and drug resistance of MM cells. VS-5584 is a novel agent, with specific and equipotent activity against mTOR and all 4 Class I PI3K isoforms, without relevant activity on 400 other lipid and protein kinases. Here we report that VS-5584 is highly efficacious against a wide panel of MM cells including Velcade- and Doxorubucin- resistant cell lines. This efficacy is maintained even in the presence of additional MM growth factors, IL-6 and IGF-1, and seems independent of PTEN status in the cell lines. Importantly, VS-5584 shows similar efficacy in patient myeloma cells and preferential tumor cell targeting compared to heal...
Blood
2913 Poster Board II-889 Introduction: Polycythemia vera (PV) is a myeloproliferative neoplasm (M... more 2913 Poster Board II-889 Introduction: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) in which the patients' erythroblastic lineage acquires a hyper-proliferative potential but retains normal maturation, leading to elevated hematocrit and its attendant risks. The discovery of an activating mutation (JAK2V617F) in almost all PV patients and about half of the other Ph-negative MPNs prompted the development of small-molecule JAK2 inhibitors as novel therapeutics. In preclinical translational studies, these compounds have been tested against primary hematopoietic cells in ex vivo assays such as the endogenous erythroid colony (EEC) assay or proliferation assay with erythroid progenitors (EP). Results have been mixed, with some compounds showing selective activity against JAK2V617F-bearing cells while…
Oncotarget, Jan 24, 2017
The PI3K/mTOR/AKT pathway is an integral regulator of survival and drug resistance in multiple my... more The PI3K/mTOR/AKT pathway is an integral regulator of survival and drug resistance in multiple myeloma (MM). VS-5584 was synthesized with dual-specific and equipotent activity against mTORC1/2 and all four Class I PI3K isoforms so as to durably inhibit this pathway. We show that VS-5584 is highly efficacious against MM cell lines even in the presence of IL-6 and IGF-1 and that this growth inhibition is partially dependent on Bim. Importantly, VS-5584 triggers apoptosis in patient cells with a favorable therapeutic index. Gene expression profiling revealed a VS-5584-induced upregulation of RARRES3, a class II tumor suppressor gene. MM patient databases, UAMS and APEX, show that RARRES3 is under-expressed in 11q13 subsets which correlates with the reduced effectiveness of VS-5584 in 11q13 cell lines. Silencing RARRES3 expression significantly rescues VS-5584-induced cell death and increases cyclin D2 expression but not cyclin D1 or other cyclins implying a role for RARRES3 in cell cyc...
European Journal of Cancer Supplements
Molecular Cancer Therapeutics, Nov 1, 2007
In a variety of established tumour cell lines, but also in primary mammary epithelial cells metal... more In a variety of established tumour cell lines, but also in primary mammary epithelial cells metalloprotease-dependent transactivation of the EGFR, and EGFR characteristic downstream signalling events were observed in response to stimulation with physiological concentrations of GPCR agonists such as the mitogens LPA and S1P as well as therapeutically relevant concentrations of cannabinoids. Moreover, this study reveals ADAM17 and HB-EGF as the main effectors of this mechanism in most of the cancer cell lines investigated. However, depending on the cellular context and GPCR agonist, various different members of the ADAM family are selectively recruited for specific ectodomain shedding of proAR and/or proHB-EGF and subsequent EGFR activation. Furthermore, biological responses induced by LPA or S1P such as migration in breast cancer and HNSCC cells, depend on ADAM17 and proHB-EGF/proAR function, respectively, suggesting that highly abundant GPCR ligands may play a role in tumour develop...
European Journal of Cancer Supplements, 2010