This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors.
Phase 1/2 Study of Uproleselan Added to Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia
Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age 60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.
Journal of Clinical Oncology
Naive T-Cell Depletion to Prevent GVHD: Searching for a Better Mousetrap
In the article that accompanies this editorial, Bleakley et al1 summarize their experience with three separate trials demonstrating that depletion of naïve CD45RA+ T cells from donor grafts before allogeneic hematopoietic cell transplantation is associated with very low rates of chronic graft versus host disease (cGVHD) and nonrelapse mortality (NRM). The rate of moderate-severe cGVHD in the 138 patients reported in the current article was very low (1%) with very few patients requiring long-term immune suppression. Although the rate of grade II acute GVHD was high, grade III-IV acute GVHD was observed in only 4% of patients. Most notably, the NRM was 8% at 3 years, relapse rate 23%, overall survival (OS) 78%, and GVHD-free relapse-free survival (GRFS) 68%.
Journal of the National Cancer Institute
Overcoming Obstacles in Transitions of Cancer Survivor Care
Morgans AK, Partridge AH
The last several decades have witnessed a dramatic revolution in the approach to cancer survivorship care. In 2005 the Institute of Medicine’s (IOM) report, “From Cancer Patient to Cancer Survivor: Lost in Transition”, highlighted growing concerns that the unique needs of the cancer survivor population, at that time comprised of over 10 million individuals in the US, was understudied by our research community and underrecognized by the care delivery system. Subsequently, there has been global recognition that the experience of having had cancer has become a chronic condition for many survivors who are living for years and sometimes decades with the combined consequences of the disease and its treatment. As therapeutic advances today continue to transform those afflicted with cancer into those living with cancer or a history of cancer, the population of cancer survivors continues to grow, with 26.1 million cancer survivors projected to be living in the US alone in 2040. Attending to the medical demands of this burgeoning population requires addressing the clinical needs of people living after cancer diagnosis and treatment, adjusting care to meet evolving needs over time, and training a sufficiently sized and trained workforce to provide that care.
Regulation of GTPase Function by Autophosphorylation
Johnson CW, Seo HS, Yang MH, Geffken EA, Lakhani J, Song K, Bashyal P, Popow O, Paulo JA, Liu A, Dhe-Paganon S, Haigis KM
A unifying feature of the RAS superfamily is a conserved GTPase cycle by which these proteins transition between active and inactive states. We demonstrate that autophosphorylation of some GTPases is an intrinsic regulatory mechanism that reduces nucleotide hydrolysis and enhances nucleotide exchange, altering the on/off switch that forms the basis for their signaling functions. Using X-ray crystallography, nuclear magnetic resonance spectroscopy, binding assays, and molecular dynamics on autophosphorylated mutants of H-RAS and K-RAS, we show that phosphoryl transfer from GTP requires dynamic movement of the switch II region and that autophosphorylation promotes nucleotide exchange by opening the active site and extracting the stabilizing Mg2+. Finally, we demonstrate that autophosphorylated K-RAS exhibits altered effector interactions, including a reduced affinity for RAF proteins in mammalian cells. Thus, autophosphorylation leads to altered active site dynamics and effector interaction properties, creating a pool of GTPases that are functionally distinct from their non-phosphorylated counterparts.
Mitochondrial Variant Enrichment from High-Throughput Single-Cell RNA Sequencing Resolves Clonal Populations
Miller TE, Lareau CA, Verga JA, DePasquale EAK, Ssozi D, Ludwig LS, El Farran CA, Griffin GK, Lane AA, Love JC, Bernstein BE, Sankaran VG, van Galen P
The combination of single-cell transcriptomics with mitochondrial DNA variant detection can be used to establish lineage relationships in primary human cells, but current methods are not scalable to interrogate complex tissues. Here, we combine common 3' single-cell RNA-sequencing protocols with mitochondrial transcriptome enrichment to increase coverage by more than 50-fold, enabling high-confidence mutation detection. The method successfully identifies skewed immune-cell expansions in primary human clonal hematopoiesis.
Proceedings of the National Academy of Science of the U.S.A.
Definition of a Mouse Microglial Subset that Regulates Neuronal Development and Proinflammatory Responses in the Brain
Shen X, Qiu Y, Wight AE, Kim HJ, Cantor H
Expression of Itgax (encoding the CD11c surface protein) and Spp1 (encoding osteopontin; OPN) has been associated with activated microglia that can develop in healthy brains and some neuroinflammatory disorders. However, whether CD11c and OPN expression is a consequence of microglial activation or represents a portion of the genetic program expressed by a stable microglial subset is unknown. Here, we show that OPN production in the brain is confined to a small CD11c+ microglial subset that differentiates from CD11c- precursors in perinatal life after uptake of apoptotic neurons. Our analysis suggests that coexpression of OPN and CD11c marks a microglial subset that is expressed at birth and persists into late adult life, independent of environmental activation stimuli. Analysis of the contribution of OPN to the intrinsic functions of this CD11c+ microglial subset indicates that OPN is required for subset stability and the execution of phagocytic and proinflammatory responses, in part through OPN-dependent engagement of the Œ±VŒ?3-integrin receptor. Definition of OPN-producing CD11c+ microglia as a functional microglial subset provides insight into microglial differentiation in health and disease.
CNGPLD: Case-Control Copy-Number Analysis Using Gaussian Process Latent Difference
Shih DJH, Carter SL
Health-Related Quality of Life with Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma
Precancer and Cancer-Associated Depression and Anxiety Among Older Adults with Blood Cancers in the United States
Kuczmarski TM, Jaung T, Mancuso CE, Abel GA, Odejide OO
CA: A Cancer Journal for Clinicians
Genetic Testing in Prostate Cancer Management: Considerations Informing Primary Care
Berchuck JE, Taplin ME
"Is It Cancer or Not?" A Qualitative Exploration of Survivor Concerns Surrounding the Diagnosis and Treatment of Ductal Carcinoma in Situ
Rosenberg SM, Revette AC, Lowenstein CL, Frank ES, Partridge AH
Germline Pathogenic Variants in Cancer Risk Genes Among Patients with Thyroid Cancer and Suspected Predisposition
Kamihara J, Wassner AJ, Dalton E, Garber JE, Black MH
Patterns of Healthcare Services Among Children with Advanced Cancer in Concurrent Hospice Care
A Genome-Scale CRISPR Screen Reveals PRMT1 as a Critical Regulator of Androgen Receptor Signaling in Prostate Cancer
Tang S, Sethunath V, Metaferia NY, Nogueira MF, Gallant DS, Garner ER, Li J, Gelbard MK, Alaiwi SA, Seo JH, Hwang JH, Strathdee CA, Baca SC, AbuHammad S, Doench JG, Hahn WC, Freedman ML, Viswanathan SR
Journal of Genetic Counseling
Patterns of Germline and Somatic Testing After Universal Tumor Screening for Lynch Syndrome: A Clinical Practice Survey of Active Members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer
Rodgers-Fouche L, Perez K
Lancet Regional Health - Americas
Effectiveness Estimates of Three COVID-19 Vaccines Based on Observational Data from Puerto Rico
Antibody and T-Cell Responses to SARS-CoV-2 Vaccination in Myeloproliferative Neoplasm Patients
How J, Gallagher KME, Liu Y, Katsis K, Elder EL, Larson RC, Leick MB, Neuberg D, Maus MV, Hobbs GS
NPJ Breast Cancer
Cardiac Outcomes of Subjects on Adjuvant Trastuzumab Emtansine vs Paclitaxel in Combination with Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT) Study (TBCRC033): A Randomized Controlled Trial
Tarantino P, Tayob N, Isakoff SJ, Faggen M, Mulvey T, Hu J, Weckstein D, Constantine M, Briccetti F, Tung N, Zheng Y, Rosenberg SM, Gelber RD, Trippa L, Barry W, DeMeo M, Burstein H, Partridge A, Winer EP, Krop I, Tolaney SM
Radiotherapy and Oncology
Major Adverse Cardiac Event Risk Prediction Model Incorporating Baseline Cardiac Disease, Hypertension, and Logarithmic Left Anterior Descending Coronary Artery Radiation Dose in Lung Cancer (CHyLL)
Tjong MC, Bitterman DS, Brantley K, Nohria A, Hoffmann U, Atkins KM, Mak RH
Statistics in Medicine
A Multivariate Parametric Empirical Bayes Screening Approach for Early Detection of Hepatocellular Carcinoma Using Multiple Longitudinal Biomarkers