A5039617409- HER2/EGFR in Cancer Research
- Chronic Lymphocytic Leukemia Research
- Synthesis and pharmacology of benzodiazepine derivatives
- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- Cancer therapeutics and mechanisms
- Protein Degradation and Inhibitors
- Neuroblastoma Research and Treatments
- Prostate Cancer Treatment and Research
- Radiopharmaceutical Chemistry and Applications
- Lymphoma Diagnosis and Treatment
- Phagocytosis and Immune Regulation
- Cancer Treatment and Pharmacology
- Neuroscience and Neuropharmacology Research
- Nuclear Receptors and Signaling
- Advanced Breast Cancer Therapies
- Immunotherapy and Immune Responses
- Virus-based gene therapy research
- Ubiquitin and proteasome pathways
- RNA Interference and Gene Delivery
- Multiple Myeloma Research and Treatments
- Acute Lymphoblastic Leukemia research
- Mass Spectrometry Techniques and Applications
- Chemical Synthesis and Analysis
- Cancer, Hypoxia, and Metabolism
e-Therapeutics (United Kingdom)
2018-2025
Aptevo Therapeutics (United Kingdom)
2019
Adc Therapeutics (Switzerland)
2014-2018
Memorial Sloan Kettering Cancer Center
2007-2013
University of Pisa
2006-2011
Laboratory of Molecular Genetics
2011
Kettering University
2007
Signal transducer and activator of transcription 3 (STAT3) plays a central role in the activation multiple oncogenic pathways. Splicing variant STAT3β uses an alternative acceptor site within exon 23 that leads to truncated isoform lacking C-terminal transactivation domain. Depending on context, can act as dominant-negative regulator promote apoptosis. We show modified antisense oligonucleotides targeted splicing enhancer regulates STAT3 specifically shift expression from STAT3α STAT3β....
Abstract Despite the many advances in treatment of hematologic malignancies over past decade, outcomes refractory lymphomas remain poor. One potential strategy this patient population is specific targeting IL2R-α (CD25), which overexpressed on lymphoma and leukemic cells, using antibody–drug conjugates (ADC). ADCT-301 an ADC composed human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to pyrrolobenzodiazepine (PBD) dimer warhead with...
Abstract Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. dimer SG3199 is the released warhead component of antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. was potently cytotoxic against panel human solid tumour and haematological...
Background Regulatory T cells (T regs ) contribute to an immunosuppressive tumor microenvironment. They play important role in the establishment and progression of tumors with high infiltration present a major obstacle eradication by immunotherapies. Numerous strategies have been attempted deplete or block , although their success has limited. Methods A CD25-targeted, pyrrolobenzodiazepine (PBD) dimer-based antibody–drug conjugate (ADC) was investigated for its ability induce antitumor...
Abstract AXL, a tyrosine kinase receptor that is overexpressed in many solid and hematologic malignancies, facilitates cancer progression associated with poor clinical outcomes. Importantly, drug-induced expression of AXL results resistance to conventional chemotherapy targeted therapies. Together its presence on multiple cell types the tumor immune microenvironment, these features make it an attractive therapeutic target for AXL-expressing malignancies. ADCT-601 (mipasetamab uzoptirine)...
Abstract Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic kinase (ALK)-positive, and ALK-negative, primary cutaneous breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, already in second line effective treatment options are lacking. To identify genes defining state dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known key regulators,...
A viral etiology of human breast cancer (HBC) has been postulated for decades since the identification mouse mammary tumor virus (MMTV). The detection MMTV env-like exogenous sequences (MMTVels) in 30% to 40% invasive HBCs increased attention this hypothesis. Looking MMTVels during progression may contribute a better understanding their role HBC. Herein, we analyzed HBC preinvasive lesions presence MMTVels. Samples were obtained by laser microdissection FFPE tissues: 20 usual-type ductal...
Goals of investigation:The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% decades because no effective therapies have been identified.Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target.Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) therapy PDAC.Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) 20mer peptide from VP1 coat protein...
Abstract Background Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)- and therapy resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype propose pan-neuroblastoma cell state specific targetable cell-surface proteins. Methods We characterized lines, patient-derived xenografts, patient samples as ADRN-dominant or MES-dominant to define subtype-specific...
Peripheral T cell lymphomas (PTCLs) comprise heterogeneous malignancies with limited therapeutic options. To uncover targetable vulnerabilities, we generate a collection of PTCL patient-derived tumor xenografts (PDXs) retaining histomorphology and molecular donor-tumor features over serial xenografting. PDX demonstrates remarkable heterogeneity, complex intratumor architecture, stepwise trajectories mimicking primary evolutions. Combining functional transcriptional stratification...
Abstract The hypothesis that a retrovirus homologous to the mouse mammary tumour virus (MMTV) is involved in human breast cancer aetiology has fascinated scientists from many years, but it never been convincingly demonstrated. Renewed interest this developed when an MMTV env gene‐like sequence was found 38% of tissues. Whereas some subsequent studies confirmed these findings, others did not. main reasons for discrepancy, among others, are different sensitivities and technical details current...
Abstract Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase that highly expressed in nearly all prostate cancers with the highest expression metastatic castration-resistant cancer (mCRPC). The prevalence of increased surface and constitutive internalization PSMA make it an attractive target for antibody–drug conjugate (ADC) approach to treating patients mCRPC. MEDI3726 (previously known as ADCT-401) ADC consisting engineered version anti-PSMA antibody...
Antibody-drug conjugates (ADC) represent one of the most successful therapeutic approaches introduced into clinical practice in last few years. Loncastuximab tesirine (ADCT-402) is a CD19-targeting ADC which antibody conjugated through protease cleavable dipeptide linker to pyrrolobenzodiazepine dimer warhead (SG3199). Based on results phase II study, loncastuximab was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed activity using vitro and...
ERG, a member of the ETS transcription factor family, is frequently overexpressed in prostate cancer as result its fusion to androgen-responsive Tmprss2 gene. Different genomic rearrangements and alternative splicing events around junction region lead multiple combination Tmprss2:ERG transcripts that correlate with different tumor aggressiveness, but their specific functions biological activities are still unclear. The complexity ERG expression pattern compounded by use promoters, splice...
Previously we reported that a novel αvβ6-specific peptide-drug conjugate (SG3299) could eliminate established human pancreatic ductal adenocarcinoma (PDAC) xenografts. However the development of effective therapies for PDAC, which is an essential need, must show efficacy in relevant immunocompetent animals. KPC mouse transgenic PDAC model closely recapitulates most stages unlike humans, failed to express αvβ6 on their tumours or metastases. In this study have taken KPC-derived line TB32043...
Abstract Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody–drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 a CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer–based payload tesirine. In preclinical studies, demonstrated potent,...
Abstract Antibody–drug conjugates (ADC) containing pyrrolobenzodiazepine (PBD) dimers are being evaluated clinically in both hematologic and solid tumors. These include ADCT-301 (camidanlumab tesirine) ADCT-402 (loncastuximab pivotal phase II trials that contain the payload tesirine, which releases PBD dimer warhead SG3199. An important consideration future clinical development is acquired resistance. The aim was to generate characterize resistant cell lines tumor settings. Human Karpas-299...
Summary Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant proteins that can serve as immunotherapeutic neuroblastoma, often-fatal childhood cancer the developing nervous system. We apply this approach human-derived lines (N=9)...