Outcomes of multiple myeloma patients receiving bortezomib, lenalidomide, and carfilzomib

Berenson, Ariana; Vardanyan, Suzie; David, Michael; Wang, James; Harutyunyan, Nika Manik; Gottlieb, Jillian; Halleluyan, Ran; Spektor, Tanya M.; Udd, Kyle; Eshaghian, Shahrooz; Nassir, Youram; Eades, Benjamin; Swift, Regina A.; Berenson, James R.

doi:10.1007/s00277-016-2889-2

Cited by 17 publications

(9 citation statements)

References 20 publications

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“…However, the role of ERSR in tumor progression has been much debated 48 . The success of proteasome inhibitors in the treatment of multiple myeloma patients 49 , as well as provocative data linking ER stress pathways to vemurafenib-resistant melanoma and immunotherapy sensitization, suggest that UPR/ERAD biology could be harnessed for treating metastatic melanoma 50 . Our analysis implicates both UPR and degradation pathways of the ERSR as acting downstream of KDELR3.…”

Section: Discussionmentioning

confidence: 99%

Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

et al. 2020

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Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.

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Section: Discussionmentioning

confidence: 99%

Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

et al. 2020

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“…The success of proteasome inhibitors in the treatment of multiple myeloma patients 49 , as well as provocative data linking ER stress pathways to vemurafenib-resistant melanoma and immunotherapy sensitization, suggest UPR/ERAD biology could be harnessed for treating metastatic melanoma [50][51][52][53][54] . Our analysis implicates both UPR and degradation pathways of the ERSR as acting downstream of KDELR3.…”

Section: Discussionmentioning

confidence: 99%

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Marie

Sassano

Yang

et al. 2019

Preprint

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Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene, KDELR3, whose loss impaired experimental metastasis. In contrast, KDELR1 deficiency enhanced metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover novel targetable pathways for melanoma therapy.Melanoma is an aggressive cancer that frequently progresses to metastatic proficiency. Treatment of metastatic melanoma remains a challenge, highlighting an urgent need to uncover new targets that could be used in the clinic to broaden therapeutic options. In the early 19 th century, Virchow first described cancer cells as being "embryonic-like" 1 . Developmental systems have since proven useful to study melanoma, and melanoma cell plasticity appears to be a key feature of melanoma progression. Melanocyte lineage pathways are a recurring theme in melanoma etiology, reinforcing the importance of uncovering new melanocyte developmental pathways and biology 2-13 . Here we use a genetically engineered mouse (GEM), designed to facilitate the isolation and analysis of developing melanocytes (melanoblasts), to attempt to uncover new targets relevant to melanoma metastasis.Melanocytes are neural crest-derived cells whose development necessitates extensive migration/invasion to populate the skin and other sites 14 . This process requires melanoblasts to adopt a migratory phenotype, to interact with and survive in foreign microenvironments and to colonize distant sites − functions that are analogous to metastatic competence 15 . To complete these processes, the cell may encounter numerous cellular stressors, such as shear stress, nutrient deprivation, hypoxia, lipid stress and oxidative stress 16 . The cellular impact of these stressors converges at the Endoplasmic Reticulum (ER), the organelle tied closely to protein synthesis and responsible for correct protein folding, protein quality control and post-translational modifications.Stress stimuli can result in aberrant ER function, a build-up of unfolded/misfolded proteins (ER stress), and an overwhelmed system. The ER can therefore be viewed as an exquisitely sensitive stress sensor. Upon ER stress insult, the ER launches an immediate counter measure known as of the Unfolded Protein Response (UPR) 17 . T...

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“…While proteasome inhibitors such as bortezomib have achieved improved outcomes when combined with traditional regimens such as lenalidomide, refractory and bortezomib-resistant MM still present a significant problem for patient prognosis. 1 , 2 , 3 …”

Section: Introductionmentioning

confidence: 99%

A compound chimeric antigen receptor strategy for targeting multiple myeloma

Chen¹,

Wada²,

Pinz³

et al. 2017

Leukemia

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Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

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Outcomes of multiple myeloma patients receiving bortezomib, lenalidomide, and carfilzomib

Cited by 17 publications

References 20 publications

Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

A compound chimeric antigen receptor strategy for targeting multiple myeloma

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