Browsing by Author "Kuzel, Timothy M."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition
    (Springer Nature, 2021-03-17) Masood, Ashiq; Christ, Trevor; Asif, Samia; Rajakumar, Priya; Gustafson, Beth A.; Shune, Leyla O.; Salahudeen, Ameen; Nedvad, Drew; Nanua, Suparna; Paner, Agne; Kuzel, Timothy M.; Levy, Mia; Subramanian, Janakiraman; Raza, Shahzad; Medicine, School of Medicine
    Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
  • Thumbnail Image
    Item
    Refining colorectal cancer classification and clinical stratification through a single-cell atlas
    (Springer, 2022-05-11) Khaliq, Ateeq M.; Erdogan, Cihat; Kurt, Zeyneb; Turgut, Sultan Sevgi; Grunvald, Miles W.; Rand, Tim; Khare, Sonal; Borgia, Jeffrey A.; Hayden, Dana M.; Pappas, Sam G.; Govekar, Henry R.; Kam, Audrey E.; Reiser, Jochen; Turaga, Kiran; Radovich, Milan; Zang, Yong; Qiu, Yingjie; Liu, Yunlong; Fishel, Melissa L.; Turk, Anita; Gupta, Vineet; Al-Sabti, Ram; Subramanian, Janakiraman; Kuzel, Timothy M.; Sadanandam, Anguraj; Waldron, Levi; Hussain, Arif; Saleem, Mohammad; El-Rayes, Bassel; Salahudeen, Ameen A.; Masood, Ashiq; Medicine, School of Medicine
    Background Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. Results Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. Conclusions Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.