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A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC)

Wise, David R; Pachynski, Russell K; Denmeade, Samuel R; Aggarwal, Rahul R; Deng, Jiehui; Febles, Victor Adorno; Balar, Arjun V; Economides, Minas P; Loomis, Cynthia; Selvaraj, Shanmugapriya; Haas, Michael; Kagey, Michael H; Newman, Walter; Baum, Jason; Troxel, Andrea B; Griglun, Sarah; Leis, Dayna; Yang, Nina; Aranchiy, Viktoriya; Machado, Sabrina; Waalkes, Erika; Gargano, Gabrielle; Soamchand, Nadia; Puranik, Amrutesh; Chattopadhyay, Pratip; Fedal, Ezeddin; Deng, Fang-Ming; Ren, Qinghu; Chiriboga, Luis; Melamed, Jonathan; Sirard, Cynthia A; Wong, Kwok-Kin
BACKGROUND:Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS:(combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS:18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION/CONCLUSIONS:DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.
PMID: 38341461
ISSN: 1476-5608
CID: 5635542

In Support of Magnani and Taylor

Dabbs, David J; Chiriboga, Luis A; Jasani, Bharat; Kinloch, Mary A; Miller, Keith D; Nielsen, Søren; Szabolcs, Matthias J; Torlakovic, Emina; Bogen, Steve; Parry, Suzanne; 't Hart, Nils A
PMID: 38157868
ISSN: 1543-2165
CID: 5628292

Hematoxylin and Eosin staining of PhenoCycler® Fusion flow cell slides

Shiomi, Tomoe; Eichinger, Anna; Chiriboga, Luis
Multiplexed Imaging technologies are powerful techniques that enable ultrahigh-plex spatial phenotyping of whole tissue sections at single cell spatial resolution. Co-Detection by Indexing (CODEX) multiplexing can detect up to 100 proteins using cyclic detection of DNA conjugated antibodies applied to tissue sections. However, it is necessary to correlate multiplexed fluorescent (mIF) spatial images with Hematoxylin and Eosin (H&E) stained sections post analysis. To effectively correlate mIF spatial images with H&E morphology, an (H&E) staining protocol was developed that is directly applied to the CODEX Fusion flow-cell slide after analysis allowing for direct H&E correlation and annotation with mIF images.
PMID: 37584179
ISSN: 2046-0236
CID: 5611372

Immunohistochemistry as an assay [Editorial]

Bell, Michelle; Chiriboga, Luis; Chlipala, Elizabeth; Forster, Colleen; Johnston, Jeremy; Santiago, Jerry; Schneider, Dawn; Winfrey, Shameika J; Schlosser, Brenda L; Thornton, Clare; Vidal, Elba G
PMID: 37953699
ISSN: 2046-0236
CID: 5610942

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Dolgalev, Igor; Zhou, Hua; Murrell, Nina; Le, Hortense; Sakellaropoulos, Theodore; Coudray, Nicolas; Zhu, Kelsey; Vasudevaraja, Varshini; Yeaton, Anna; Goparaju, Chandra; Li, Yonghua; Sulaiman, Imran; Tsay, Jun-Chieh J; Meyn, Peter; Mohamed, Hussein; Sydney, Iris; Shiomi, Tomoe; Ramaswami, Sitharam; Narula, Navneet; Kulicke, Ruth; Davis, Fred P; Stransky, Nicolas; Smolen, Gromoslaw A; Cheng, Wei-Yi; Cai, James; Punekar, Salman; Velcheti, Vamsidhar; Sterman, Daniel H; Poirier, J T; Neel, Ben; Wong, Kwok-Kin; Chiriboga, Luis; Heguy, Adriana; Papagiannakopoulos, Thales; Nadorp, Bettina; Snuderl, Matija; Segal, Leopoldo N; Moreira, Andre L; Pass, Harvey I; Tsirigos, Aristotelis
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
PMCID:10632519
PMID: 37938580
ISSN: 2041-1723
CID: 5609852

Automated and robust extraction of genomic DNA from various leftover blood samples

You, Jianlan; Osea, Jan; Mendoza, Sandra; Shiomi, Tomoe; Gallego, Estefania; Pham, Bernice; Kim, Angie; Sinay-Smith, Abraham; Zayas, Zasha; Neto, Antonio G; Boytard, Ludovic; Chiriboga, Luis; Cotzia, Paolo; Moreira, Andre L
With the development of genomic technologies, the isolation of genomic DNA (gDNA) from clinical samples is increasingly required for clinical diagnostics and research studies. In this study, we explored the potential of utilizing various leftover blood samples obtained from routine clinical tests as a viable source of gDNA. Using an automated method with optimized pre-treatments, we obtained gDNA from seven types of clinical leftover blood, with average yields of gDNA ranging from 3.11 ± 0.45 to 22.45 ± 4.83 μg. Additionally, we investigated the impact of storage conditions on gDNA recovery, resulting in yields of 8.62-68.08 μg when extracting gDNA from EDTA leftover blood samples stored at 4 °C for up to 13 weeks or -80 °C for up to 78 weeks. Furthermore, we successfully obtained sequenceable gDNA from both Serum Separator Tube and EDTA Tube using a 96-well format extraction, with yields ranging from 0.61 to 71.29 μg and 3.94-215.98 μg, respectively. Our findings demonstrate the feasibility of using automated high-throughput platforms for gDNA extraction from various clinical leftover blood samples with the proper pre-treatments.
PMID: 37543277
ISSN: 1096-0309
CID: 5597832

Persistent hepatitis B virus and HIV coinfections in dually humanized mice engrafted with human liver and immune system

Hogan, Glenn; Winer, Benjamin Y; Ahodantin, James; Sellau, Julie; Huang, Tiffany; Douam, Florian; Funaki, Masaya; Chiriboga, Luis; Su, Lishan; Ploss, Alexander
Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), remains a major medical problem. HBV has a high propensity for progressing to chronicity and can result in severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. CHB patients frequently present with viral coinfection, including human immunodeficiency virus type (HIV) and hepatitis delta virus. About 10% of chronic HIV carriers are also persistently infected with HBV, which can result in more exacerbated liver disease. Mechanistic studies of HBV-induced immune responses and pathogenesis, which could be significantly influenced by HIV infection, have been hampered by the scarcity of immunocompetent animal models. Here, we demonstrate that humanized mice dually engrafted with components of a human immune system and a human liver supported HBV infection, which was partially controlled by human immune cells, as evidenced by lower levels of serum viremia and HBV replication intermediates in the liver. HBV infection resulted in priming and expansion of human HLA-restricted CD8+ T cells, which acquired an activated phenotype. Notably, our dually humanized mice support persistent coinfections with HBV and HIV, which opens opportunities for analyzing immune dysregulation during HBV and HIV coinfection, and preclinical testing of novel immunotherapeutics.
PMID: 37403703
ISSN: 1096-9071
CID: 5537292

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems

Castillo, Rochelle L; Sidhu, Ikjot; Dolgalev, Igor; Chu, Tinyi; Prystupa, Aleksandr; Subudhi, Ipsita; Yan, Di; Konieczny, Piotr; Hsieh, Brandon; Haberman, Rebecca H; Selvaraj, Shanmugapriya; Shiomi, Tomoe; Medina, Rhina; Girija, Parvathy Vasudevanpillai; Heguy, Adriana; Loomis, Cynthia A; Chiriboga, Luis; Ritchlin, Christopher; Garcia-Hernandez, Maria De La Luz; Carucci, John; Meehan, Shane A; Neimann, Andrea L; Gudjonsson, Johann E; Scher, Jose U; Naik, Shruti
Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.
PMID: 37267384
ISSN: 2470-9468
CID: 5536642

Histopathology of the Mitral Valve Residual Leaflet in Obstructive Hypertrophic Cardiomyopathy

Troy, Aaron L; Narula, Navneet; Massera, Daniele; Adlestein, Elizabeth; Alvarez, Isabel Castro; Janssen, Paul M L; Moreira, Andre L; Olivotto, Iacopo; Stepanovic, Alexandra; Thomas, Kristen; Zeck, Briana; Chiriboga, Luis; Swistel, Daniel G; Sherrid, Mark V
BACKGROUND:Mitral valve (MV) elongation is a primary hypertrophic cardiomyopathy (HCM) phenotype and contributes to obstruction. The residual MV leaflet that protrudes past the coaptation point is especially susceptible to flow-drag and systolic anterior motion. Histopathological features of MVs in obstructive hypertrophic cardiomyopathy (OHCM), and of residual leaflets specifically, are unknown. OBJECTIVES/OBJECTIVE:The purpose of this study was to characterize gross, structural, and cellular histopathologic features of MV residual leaflets in OHCM. On a cellular-level, we assessed for developmental dysregulation of epicardium-derived cell (EPDC) differentiation, adaptive endocardial-to-mesenchymal transition and valvular interstitial cell proliferation, and genetically-driven persistence of cardiomyocytes in the valve. METHODS:Structural and immunohistochemical staining were performed on 22 residual leaflets excised as ancillary procedures during myectomy, and compared with 11 control leaflets from deceased patients with normal hearts. Structural components were assessed with hematoxylin and eosin, trichrome, and elastic stains. We stained for EPDCs, EPDC paracrine signaling, valvular interstitial cells, endocardial-to-mesenchymal transition, and cardiomyocytes. RESULTS:= 0.08). No markers of primary cellular processes were identified. CONCLUSIONS:MV residual leaflets in HCM were characterized by histologic findings that were likely secondary to chronic hemodynamic stress and may further increase susceptibility to systolic anterior motion.
PMCID:10306242
PMID: 37383048
ISSN: 2772-963x
CID: 5540432

Microthrombi in Gastrointestinal Tissues Associated with Local SARS-CoV-2 Infection in COVID-19 Patients [Meeting Abstract]

Hoskoppal, Deepthi; Saberi, Shahram; Chiriboga, Luis; Zhao, Chaohui; Sarkar, Suparna; Cao, Wenqing (Wendy)
ISI:000990969801092
ISSN: 0023-6837
CID: 5525692