Atkinson Noland and Associates (United States)

Abstract Activating MAPK pathway mutations, found in >30% of all human tumors, are frequently associated with poor outcomes. Several MAPK pathway targeted drugs are approved but single agent activity is modest, supporting the need for rational targeted combinations to improve outcomes. Multiple studies propose synthetic lethality between Class I HDAC inhibitors and MAPK pathway inhibitors in MAPK pathway mutated cancers, due to a combined effect of inhibiting double-stranded DNA repair and other survival pathways to drive apoptosis. The use of HDACi has been challenged by poor potency, selectivity, safety and convenience, highlighting the need for a better HDACi in the clinic. Bocodepsin, a potent class I-selective oral HDACi, is currently in a phase 1b/2 trial in combination with binimetinib in patients with NRAS mutant melanoma. The clinical profile shows exposure consistent with preclinical activity with strong pharmacodynamic activity at tolerated doses. OKI-005, a bocodepsin analog optimized for in vitro activity, produces the same active metabolite as bocodepsin. To explore the potential for broad application of bocodepsin combinations, we evaluated OKI-005 in combination with the MEK inhibitor binimetinib in a 72H in vitro proliferation screen of 89 cell lines covering a range of tumor types, MAPK pathway mutations, and co-mutations. Net cell killing with the combination vs. single agents was evaluated at clinically relevant doses. Combination activity was observed in tumor types that commonly harbor activating MAPK pathway mutations, including melanoma (6/13, 46%), pancreatic (3/5, 60%), lung (10/22, 45%) and colon (8/13, 62%). Among these, single agent binimetinib activity was observed in only 1/53. The combination response rate in colon cancer models was of note, as single agent MAPK pathway inhibitors are typically inactive in colon cancers. Activity was independent of the activating MAPK pathway mutation: combination activity was observed in lines with KRAS (13/24, 52%), NRAS (8/12, 67%) and BRAF (7/13, 54%) mutations. These findings translated to combinations with other MAPK inhibitors in vitro and in vivo. In vitro, OKI-005 exhibited enhanced activity in combination with KRAS inhibitors and with the ERK inhibitor GDC-0994. 25 of the 89 tumor lines were evaluated in combination with GDC-0994, and the profile of inhibition was identical to that with binimetinib. In vivo, the combination of binimetinib + bocodepsin led to 9/10 regressions in the NRAS mutant melanoma model SK-MEL-2, vs. 0/10 and 2/10 with binimetininb and bocodepsin, respectively. The combination of sotorasib + bocodepsin led to deeper regressions, vs. single agent sotorasib, in the KRAS mutant NSCLC model H358, and greater response in the KRAS mutant NSCLC model H2122. Combination activity was associated with increases in cleaved PARP and p-gH2AX, markers of DNA damage induction and apoptosis. These data demonstrate the potential for bocodepsin to synergize with MAPK pathway inhibitors across multiple indications in tumors that harbor MAPK pathway mutations. Citation Format: Rich Woessner, Maria Hoh, James Winkler, Tony Piscopio, Duncan Walker. The class I selective, oral HDAC inhibitor bocodepsin enhances the response to MAPK pathway inhibitors in multiple tumor types with mutations in MAPK pathway signaling proteins [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A091.

Histone deacetylases (HDACs) play critical roles in epigenomic regulation, and histone acetylation is dysregulated in many human cancers. Although HDAC inhibitors are active in T-cell lymphomas, poor isoform selectivity, narrow therapeutic indices, and a deficiency of reliable biomarkers may contribute to the lack of efficacy in solid tumors. In this article, we report the discovery and preclinical development of the novel, orally bioavailable, class-I-selective HDAC inhibitor, OKI-179. OKI-179 and its cell active predecessor OKI-005 are thioester prodrugs of the active metabolite OKI-006, a unique congener of the natural product HDAC inhibitor largazole. OKI-006, OKI-005, and subsequently OKI-179, were developed through a lead candidate optimization program designed to enhance physiochemical properties without eroding potency and selectivity relative to largazole. OKI-005 displays antiproliferative activity in vitro with induction of apoptosis and increased histone acetylation, consistent with target engagement. OKI-179 showed antitumor activity in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. Based on its potency, desirable class I HDAC inhibition profile, oral bioavailability, and efficacy against a broad range of solid tumors, OKI-179 is currently being evaluated in a first-in-human phase I clinical trial with plans for continued clinical development in solid tumor and hematologic malignancies.

PD1 blockade is effective in a subset of patients with B-cell lymphoma (e.g., classical-Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To study PD1 resistance, we used an isoform-selective histone deacetylase inhibitor (HDACi; OKI-179), and a mouse mature B-cell lymphoma, G1XP lymphoma, immunosuppressive features of which resemble those of human B-cell lymphomas, including downregulation of MHC class I and II, exhaustion of CD8+ and CD4+ tumor-infiltrating lymphocytes (TIL), and PD1-blockade resistance. Using two lymphoma models, we show that treatment of B-cell lymphomas refractory to PD1 blockade with both OKI-179 and anti-PD1 inhibited growth; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated with MHC class II expression level. We conclude that OKI-179 sensitizes lymphomas to PD1-blockade by enhancing tumor immunogenicity. In addition, we found that different HDACis exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas. Our study highlights the immunologic effects of HDACis on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and the individual profiles of HDACi.

Racism persists in the work we do as architects, architecture students, and architectural educators. In this paper, we combine sociological theories of colorblind racism and white hegemony with an analysis of architectural design processes. We draw from writings, poetry, imagery, and renderings as media that aid in making architecture’s racial discrimination visible. We propose ways of thinking about colorblind racism in design that we hope will aid design practioners, students, and teachers in countering hegemonic racist ideologies that are present in our work. We consider ways that in our practices and our teaching, we conceptualize space as colorblind, we render those spaces as white, hegemonic, and normative, and we disengage when those spaces sustain racism. We argue that our failure to see the racialization of the spaces we imagine is an expression of colorblind racism.

This paper describes results of a testing program to study behavior of confined masonry wall panels subjected to earthquake loading including observations regarding their shear strength, ductility, and failure mechanism when subjected to in-plane loading. Often in construction practice, confined masonry is built with either toothed reinforced concrete frame elements or smooth reinforced concrete elements cast around the masonry wall panel. Through experimental tests, this study found that the structural integrity of a confined masonry system is especially sensitive to the compression forces confining the wall from the surrounding frame. In addition, the failure mechanism for this type of composite masonry shear wall is similar to one of the behavior modes of reinforced concrete masonry infill walls.

Erin McKeon is associate director of government affairs and Rose Gonzales is director of government affairs at the ANA.

Rose Gonzalez is director of government affairs and Margaret Kay is periodicals manager at the ANA.

Acoustic tomography is an established nondestructive evaluation (NDE) technology that can be used to image the interior of large grained building materials such as concrete or masonry. A literature search focusing on geotomography and tomographic applications in infrastructure NDE was performed. This paper highlights some historical publications of interest as well as illustrates the general theory of acoustic tomography. A questionnaire was sent to the transportation departments of the 50 states. The questionnaire is general in scope, written to ascertain which NDE methods the states are using, and to identify their concerns and interests. The questionnaire asks the state officials whether the tomography technique seemed useful. The results of this question are presented in this paper. A data acquisition and processing system has been developed to facilitate an acoustic tomography system. Using an array of transducers and data processing software, the system is fast enough to internally image concrete structures in the field. Laboratory results and field applications are presented in the form of three case studies. The technique is shown to be useful for imaging of cracks, cold joints, and voids in concrete structures.