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Boland, Genevieve

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Boland

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Genevieve

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Boland, Genevieve
Author's Publications: search.filters.isAuthorOfPublication.83590119-2d02-4b23-9d15-22e9e36b7993

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    Evolution of Delayed Resistance to Immunotherapy in a Melanoma Responder
    (Springer Nature, 2021-05-03) Liu, David; Lin, Jia-Ren; Robitschek, Emily; Kasumova, Gyulnara; Heyde, Alexander; Shi, Alvin; Kraya, Adam; Zhang, Gao; Moll, Tabea; Frederick, Dennie; Chen, Yu-An; Schapiro, Denis; Ho, Li-Lun; Bi, Kevin; Sahu, Avinash; Mei, Shaolin; Miao, Benchun; Sharova, Tatyana; Alvarez-Breckenridge, Christopher; Stocking, Jackson; Kim, Tommy; Fadden, Riley; Lawrence, Donald; Hoang, Mai; Cahill, Daniel; Maleh Mir, Mohsen; Nowak, Martin; Brastianos, Priscilla; Lian, Christine; Ruppin, Eytan; Izar, Benjamin; Herlyn, Meenhard; Van Allen, Eliezer; Nathanson, Katherine; Flaherty, Keith; Sullivan, Ryan; Kellis, Manolis; Sorger, Peter; Boland, Genevieve
    Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a metastatic melanoma patient with exceptional response followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of 7 lineages with multiple convergent, but independent resistance-associated alterations (RAAs). All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNAseq and highly-multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition amongst different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR-High tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated 2 distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated, neural crest tumor population in melanoma immunotherapy resistance, and describes site specific differences in tumor-immune interactions via longitudinal analysis of a melanoma patient with an unusual clinical course.
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    Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma
    (John Wiley and Sons Inc., 2018) Echevarría‐Vargas, Ileabett M; Reyes‐Uribe, Patricia I; Guterres, Adam N; Yin, Xiangfan; Kossenkov, Andrew V; Liu, Qin; Zhang, Gao; Krepler, Clemens; Cheng, Chaoran; Wei, Zhi; Somasundaram, Rajasekharan; Karakousis, Giorgos; Xu, Wei; Morrissette, Jennifer JD; Lu, Yiling; Mills, Gordon B; Sullivan, Ryan; Benchun, Miao; Frederick, Dennie T; Boland, Genevieve; Flaherty, Keith; Weeraratna, Ashani T; Herlyn, Meenhard; Amaravadi, Ravi; Schuchter, Lynn M; Burd, Christin E; Aplin, Andrew E; Xu, Xiaowei; Villanueva, Jessie
    Abstract Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS‐mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS‐mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS‐mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co‐targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment‐resistant tumor types.
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    Clinical next generation sequencing to identify actionable aberrations in a phase I program
    (Impact Journals LLC, 2015) Boland, Genevieve; Piha-Paul, Sarina A.; Subbiah, Vivek; Routbort, Mark; Herbrich, Shelley M.; Baggerly, Keith; Patel, Keyur P.; Brusco, Lauren; Horombe, Chacha; Naing, Aung; Fu, Siqing; Hong, David S.; Janku, Filip; Johnson, Amber; Broaddus, Russell; Luthra, Raja; Shaw, Kenna; Mendelsohn, John; Mills, Gordon B.; Meric-Bernstam, Funda
    Purpose We determined the frequency of recurrent hotspot mutations in 46 cancer-related genes across tumor histologies in patients with advanced cancer. Methods: We reviewed data from 500 consecutive patients who underwent genomic profiling on an IRB-approved prospective clinical protocol in the Phase I program at the MD Anderson Cancer Center. Archival tumor DNA was tested for 740 hotspot mutations in 46 genes (Ampli-Seq Cancer Panel; Life Technologies, CA). Results: Of the 500 patients, 362 had at least one reported mutation/variant. The most common likely somatic mutations were within TP53 (36%), KRAS (11%), and PIK3CA (9%) genes. Sarcoma (20%) and kidney (30%) had the lowest proportion of likely somatic mutations detected, while pancreas (100%), colorectal (89%), melanoma (86%), and endometrial (75%) had the highest. There was high concordance in 62 patients with paired primary tumors and metastases analyzed. 151 (30%) patients had alterations in potentially actionable genes. 37 tumor types were enrolled; both rare actionable mutations in common tumor types and actionable mutations in rare tumor types were identified. Conclusion: Multiplex testing in the CLIA environment facilitates genomic characterization across multiple tumor lineages and identification of novel opportunities for genotype-driven trials.
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    Metastatic melanoma with spontaneous complete regression of a thick primary lesion
    (Elsevier, 2016) Khosravi, Hasan; Akabane, Andressa L.; Alloo, Allireza; Nazarian, Rosalynn; Boland, Genevieve
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    Resistance to checkpoint blockade therapy through inactivation of antigen presentation
    (Nature Publishing Group UK, 2017) Sade-Feldman, Moshe; Jiao, Yunxin J.; Chen, Jonathan; Rooney, Michael S.; Barzily-Rokni, Michal; Eliane, Jean-Pierre; Bjorgaard, Stacey L.; Hammond, Marc R.; Vitzthum, Hans; Blackmon, Shauna M.; Frederick, Dennie T.; Hazar-Rethinam, Mehlika; Nadres, Brandon A.; Van Seventer, Emily E.; Shukla, Sachet A.; Yizhak, Keren; Ray, John P.; Rosebrock, Daniel; Livitz, Dimitri; Adalsteinsson, Viktor; Getz, Gad; Duncan, Lyn; Li, Bo; Corcoran, Ryan; Lawrence, Donald; Stemmer-Rachamimov, Anat; Boland, Genevieve; Landau, Dan A.; Flaherty, Keith; Sullivan, Ryan; Hacohen, Nir
    Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.