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. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: [email protected]. Note that there is a two-week lag in publishing, so this issue reflects papers with a PubMed publication date between January 16 through January 31.  

For more about Dana-Farber science, tune in to the Unraveled Podcast. The second season is now available at dana-farber.org/unraveled, or wherever you get your podcasts. 

Blood

A MIR17HG-Derived Long Noncoding RNA Provides an Essential Chromatin Scaffold for Protein Interaction and Myeloma Growth

Morelli E, Fulciniti M, Samur MK, Wert-Lamas L, Gulla A, Aktas-Samur A, Talluri S, Bianchi G, Johnstone M, Liu N, Gramegna D, Maisano D, Tai YT, Chauhan D, Hideshima T, Shammas MA, Anderson KC, Novina CD, Munshi NC

Long noncoding RNAs (lncRNAs) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell-growth dependency to lncRNA genes in multiple myeloma (MM) and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that an MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell-growth dependency acting in a microRNA- and DROSHA-independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1. Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent antitumor effects both in-vitro and in-vivo in 3 preclinical animal models, including a clinically relevant patient-derived xenograft NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.

Blood

Mechanisms of Response and Resistance to Combined Decitabine and Ipilimumab for Advanced Myeloid Disease

Penter L, Liu Y, Wolff JO, Yang L, Taing L, Jhaveri A, Southard J, Cullen N, Pfaff KL, Cieri N,
Oliveira G, Ranasinghe S, Leonard R, Robertson T, Morgan EA, Li S, Rodig SJ, Cibulskis C,
Gabriel S, Ritz J, Neuberg D, Hodi FS, Davids MS, Livak KJ, Altreuter J, Michor F, Soiffer RJ,
Garcia JS, Wu CJ

The challenge of eradicating leukemia for patients with acute myelogenous leukemia (AML) following initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 (NCT02890329) study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either following allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naive setting. Integrative transcriptome-based analysis of 304,961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent following ipilimumab exposure, which altered CD4+ T cell gene expression, in line with ongoing T cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemia cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses.

Blood

The End of the Beginning: Application of Single-Cell Sequencing to Chronic Lymphocytic Leukemia

Nagler A, Wu CJ

Single-cell analysis has emerged over the past decade as a transformative technology informative for the systematic analysis of complex cell populations such as in cancers and the tumor immune microenvironment. The methodologic and analytical advancements in this realm have evolved rapidly, scaling from but a few cells at its outset to the current capabilities of processing and analyzing hundreds of thousands of individual cells at a time. The types of profiling attainable at individual cell resolution now range from genetic and transcriptomic characterization and extend to epigenomic and spatial analysis. Additionally, the increasing ability to achieve multiomic integration of these data layers now yields ever richer insights into diverse molecular disease subtypes and the patterns of cellular circuitry on a per-cancer basis. Over the years, chronic lymphocytic leukemia (CLL) consistently has been at the forefront of genomic investigation, given the ready accessibility of pure leukemia cells and immune cells from circulating blood of patients with this disease. Herein, we review the recent forays into the application of single-cell analysis to CLL, which are already revealing a new understanding of the natural progression of CLL, the impact of novel therapies, and the interactions with coevolving nonmalignant immune cell populations. As we emerge from the end of the beginning of this technologic revolution, CLL stands poised to reap the benefits of single-cell analysis from the standpoints of uncovering fresh fundamental biological knowledge and of providing a path to devising regimens of personalized diagnosis, treatment, and monitoring.

Journal of Clinical Oncology

A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer

Konstantinopoulos PA, Lee EK, Xiong N, Krasner C, Campos S, Kolin DL, Liu JF, Horowitz N,
Wright AA, Bouberhan S, Penson RT, Yeku O, Bowes B, Needham H, Hayes M, Sawyer H, Polak M, Shea M, Cheng SC, Castro C, Matulonis UA

PURPOSE: -catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting.bEstrogen receptor (ER)-positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/

METHODS: We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months.

RESULTS: At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response (CTNNB1, KRAS, and CDKN2A mutations) or absence of response (TP53 mutations), which require independent validation.

CONCLUSION: Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.

Journal of Clinical Oncology

Efficacy and Safety of Mirvetuximab Soravtansine in Patients with Platinum-Resistant Ovarian Cancer with High Folate Receptor Alpha Expression: Results from the SORAYA Study

Matulonis UA

PURPOSE: ). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC.a (FRaSingle-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor

METHODS: -high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point.aSORAYA enrolled FR

RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively.

CONCLUSION: -high PROC who had received up to three prior therapies, including bevacizumab, aMIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRrepresenting an important advance for this biomarker-selected population.

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