Robert A. Mullinax

TRLS-12 PD-1 AND LAG3 COMBINATION BLOCKADE THERAPY REDUCES MELANOMA BRAIN METASTATIC TUMOR GROWTH IN PRECLINICAL MODELS AND IS ABROGATED BY NEUTROPHIL INFILTRATION

David Haixiang Peng, Mariah Williams, Joseph R. Daniele, Ben Bivona et autres

Abstract BACKGROUND Previous clinical trials with PD-1 and LAG3 combination blockade showed significantly improved survival in patients with advanced melanoma. However, the efficacy of the immunotherapy combination has not been evaluated in melanoma patients with brain metastasis, which is frequently observed in …

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Data from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

Yuting Sun, Brooke A. Meyers, Barbara Czakó, Paul G. Leonard et autres

Abstract Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical …

Data from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

Yuting Sun, Brooke A. Meyers, Barbara Czakó, Paul G. Leonard et autres

Abstract Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical …

Supplementary information from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

Yuting Sun, Brooke A. Meyers, Barbara Czakó, Paul G. Leonard et autres

Supplementary Materials and Methods Supplementary References Tables S1 to S3 and legends Figures S1 to S4 and legends

Supplementary information from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

Yuting Sun, Brooke A. Meyers, Barbara Czakó, Paul G. Leonard et autres

Supplementary Materials and Methods Supplementary References Tables S1 to S3 and legends Figures S1 to S4 and legends

Multi-disciplinary efforts to evaluate the therapeutic potential of CDK11, a novel transcription associated cyclin dependent kinase.

Christopher L. Carroll, Jan Reiling, Jeffrey J. Kovacs, Michael Bradley et autres

Conclusions• CDK11 was identified from an in vivo functional genomics screen as a novel therapeutic target in PCAD patients.• Pharmacological inhibition with potent and selective tool compounds revealed a disconnect with genetic validation data.• Minimal tumor growth inhibition was observed in mouse …

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Abstract 985: BI 905711 selectively induces apoptosis and anti-tumor response in TRAILR2/CDH17- expressing pancreatic cancer models

Jing Dong J Han, Annette A. Machado, Mikhila Mahendra, Joseph R. Daniele et autres

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal adult cancers with an average 5-year survival rate of less than 10% due in part to the limited number of effective therapies. Activation of TRAILR2 (Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand …

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Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer

Akira Inoue, Frederick Scott Robinson, Rosalba Minelli, Hideo Tomihara et autres

BACKGROUND & AIMS: Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. METHODS: To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we …

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Discovery of IPN60090, a Clinical Stage Selective Glutaminase‑1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

Michael Soth, Kang Le, Maria Emilia Di Francesco, Matthew M. Hamilton et autres

Abstract Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing …

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Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

Yuting Sun, Brooke A. Meyers, Barbara Czakó, Paul G. Leonard et autres

Abstract Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical …

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Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

Barbara Czakó, Joseph R. Marszalek, Jason P. Burke, Pijus Kumar Mandal et autres

Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. …

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Abstract C036: Discovery of IACS-13909, an allosteric SHP2 inhibitor that overcomes multiple mechanisms underlying osimertinib resistance

Yuting Sun, Brooke A. Meyers, Sarah B. Johnson, Angela L. Harris et autres

Abstract Osimertinib, a third generation EGFR inhibitor, is a front-line therapy for EGFR mutated non-small lung cancer (NSCLC). The long-term effectiveness of osimertinib is limited by acquired resistance. Clinically identified resistance mechanisms include EGFR-dependent mechanisms such as mutations on EGFR that preclude …

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