Dana-Farber Research News 10.15.2024

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October 15, 2024

This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from September 16 through September 30.

If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing dfciresearchnews@dfci.harvard.edu.

For more about Dana-Farber science, tune in to our Unraveled podcast, available at dana-farber.org/unraveled, or wherever you get your podcasts.

Blood

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CRISPR-Based Rapid Molecular Diagnostic Tests for Fusion-Driven Leukemias

Vedula RS, Karp HQ, Koob J, Lim F, Garcia JS, Winer ES, Luskin MR, Kim AS, Zhang F, Lindsley RC

Fusion oncogenes can be cancer-defining molecular alterations that are essential for diagnosis and therapy selection.1,2 Rapid and accessible molecular diagnostics for fusion-driven leukemias such as acute promyelocytic leukemia (APL), Philadelphia chromosome-positive acute lymphoblastic leukemia, and chronic myeloid leukemia (CML) are unavailable, creating a barrier to timely diagnosis and effective targeted therapy in many health care settings, including community hospitals and low-resource environments. We developed CRISPR-based RNA-fusion transcript detection assays using SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) for the diagnosis of fusion-driven leukemias. We validated these assays using diagnostic samples from patients with APL and CML from academic centers and dried blood spots from low-resource environments, demonstrating 100% sensitivity and specificity. We identified assay optimizations to enable the use of these tests outside of tertiary cancer centers and clinical laboratories, enhancing the potential impact of this technology. Rapid point-of-care diagnostics can improve outcomes for patients with cancer by expanding access to therapies for highly treatable diseases that would otherwise lead to serious adverse outcomes due to delayed or missed diagnoses.

 

Blood

Fixed-Duration Pirtobrutinib Plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: The Phase 1b BRUIN Trial

Brown JR

Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ?3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.

 

Blood

Sustained Benefit of Zanubrutinib vs Ibrutinib in Patients With R/R CLL/SLL: Final Comparative Analysis of ALPINE

Brown JR

ALPINE (NCT03734016) established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL); here we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n=327) or ibrutinib (n=325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (HR: 0.68 [95% CI, 0.54-0.84]), including in patients with del(17p)/TP53 mutation (HR: 0.51 [95% CI, 0.33-0.78]) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). While median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR: 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common non-hematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs six cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile.

 

Blood

The Current Landscape of Frontline Large B-Cell Lymphoma Trials

Qualls DA, Armand P

At least 25-35% of patients with large B cell lymphoma (LBCL) are not cured with frontline treatment, with generally poor subsequent outcomes. This motivates ongoing and intense interest in improving the frontline treatment of this disease. R-CHOP has remained the standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and only recently has a novel regimen (Pola-R-CHP) challenged its supremacy. Fortunately, at least 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are underway. They differ not only in the therapy evaluated in the experimental arm, but in the choice of control arm, primary endpoint, and patient selection strategy, with some targeting specific biologic subtypes, some focusing on specific high-risk patient populations, and others enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor DNA are also underway. While this variety of approaches provides a welcome increase in the overall likelihood of success, it will also present challenges if several of these trials are successful and we must choose among multiple potential treatment options that were not all tested in the same fashion. In this review, we summarize the main ongoing frontline randomized trials and discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years.

 

Cancer Cell

GABAergic Neuronal Lineage Development Determines Clinically Actionable Targets in Diffuse Hemispheric Glioma, H3G34-Mutant

Ilon L, Cruzeiro GAV, Hack OA, Shaw ML, Panditharatna E, Englinger B, Mire HM, Jiang L, Nascimento A, LaBelle J, Haase R, Rozowsky J, Neyazi S, Baumgartner AC, Castellani S, Hoffman SE, Cameron A, Morrow M, Nguyen QD, Rota C, Ligon KL, Alexandrescu S, Gojo J, Filbin MG

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

 

Journal of Clinical Oncology

Individualized Local Recurrence Estimates for Ductal Carcinoma In Situ

Warren LEG, Bellon JR

In 2020, there were 2.26 million new cases of breast cancer worldwide, making it the most common cancer in the world excluding nonmelanoma skin cancers. In countries with robust screening programs, ductal carcinoma in situ (DCIS) accounts for 15%-25% of these cases. The American Cancer Society estimates that there are over 51,000 new cases of DCIS in the United States annually. Although DCIS is considered to be a precursor to invasive breast cancer, there is a variable likelihood of progression, with studies suggesting that up to 50% of DCIS may not progress to invasive cancer. Given the variability in disease course, there has been increasing interest in individualizing treatment strategies to minimize overtreatment. Proposed de-escalation strategies have included omission of surgery, for example, in the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial (ClinicalTrials.gov identifier: NCT02926911). Despite shorter treatment courses and reduced toxicities with modern radiation planning, omission of adjuvant radiation therapy (RT) to avoid acute and long-term side effects remains of interest.

 

JAMA

The Promise and Perils of Diversity Action Plans for Clinical Trials

Varma T, Bierer BE, Hantel A

Enacted on December 29, 2022, the Food and Drug Omnibus Reform Act of 2022 (FDORA) included novel provisions for advancing clinical trial diversity. Specifically, FDORA granted the US Food and Drug Administration (FDA) the statutory authority to require drug and device sponsors to submit diversity action plans (DAPs) that must specify enrollment goals by race, ethnicity, sex, and age. Although Congress had previously enacted legislation encouraging clinical trial diversity, this was the first time it required clinical trial sponsors to develop plans for advancing demographic representation. Following the FDORA mandate, the FDA revised and published draft guidance on the format and content of DAPs on June 26, 2024.

 

Nature

Transferrin Receptor Targeting Chimeras for Membrane Protein Degradation

Zhang D, Duque-Jimenez J, Facchinetti F, Brixi G, Rhee K, Feng WW, Jänne PA, Zhou X

Cancer cells require high levels of iron for rapid proliferation, leading to significant upregulation of cell-surface transferrin receptor 1 (TfR1), which mediates iron uptake by binding to the iron-carrying protein transferrin1-3. Leveraging this phenomenon and the fast endocytosis rate of TfR1 (refs. 4,5), we developed transferrin receptor targeting chimeras (TransTACs), a heterobispecific antibody modality for membrane protein degradation. TransTACs are engineered to drive rapid co-internalization of a target protein of interest and TfR1 from the cell surface, and to enable target protein entry into the lysosomal degradation pathway. We show that TransTACs can efficiently degrade a diverse range of single-pass, multi-pass, native or synthetic membrane proteins, including epidermal growth factor receptor, programmed cell death 1 ligand 1, cluster of differentiation 20 and chimeric antigen receptor. In example applications, TransTACs enabled the reversible control of human primary chimeric antigen receptor T cells and the targeting of drug-resistant epidermal growth factor receptor-driven lung cancer with the exon 19 deletion/T790M/C797S mutations in a mouse xenograft model. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and targeted cancer therapy.

 

Nature Communications

NEAT1 Modulates the TIRR/53BP1 Complex to Maintain Genome Integrity

Kilgas S, Syed A, Swift ML, Roychoudhury S, Sarkar A, Wilkins S, Quigley M, Drané P, Chowdhury D

Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1's function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1's function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases.

 

New England Journal of Medicine

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors

Chan JA, Meyerhardt JA

BACKGROUND: Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear.

METHODS: We enrolled two independent cohorts of patients – those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors – who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety.

RESULTS: In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events.

CONCLUSIONS: Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).

 

Proceedings of the National Academy of Sciences of the U.S.A.

Total Loss of VHL Gene Function Impairs Neuroendocrine Cancer Cell Fitness Due to Excessive HIF2? Activity

Abu-Remaileh M, Persky NS, Lee Y, Root DE, Kaelin WG Jr

Loss-of-function germline von Hippel-Lindau (VHL) tumor suppressor mutations cause VHL disease, which predisposes individuals to kidney cancer, hemangioblastomas, and paragangliomas. The risk that a given VHL disease family will manifest some or all these tumor types is profoundly influenced by the VHL allele it carries. For example, almost all VHL disease families that develop paraganglioma have missense VHL mutations. VHL families with null VHL alleles develop kidney cancer and hemangioblastomas without a high risk of paraganglioma. The latter is surprising because the VHL gene product, pVHL, suppresses the HIF2 transcription factor and gain-of-function HIF2 mutations are also linked to paraganglioma. Paragangliomas arise from the sympathetic or parasympathetic nervous system. Given the lack of human paraganglioma cell lines, we studied the effects of inactivating VHL in neuroblastoma cell lines, which also arise from the sympathetic nervous system. We found that total loss of pVHL function profoundly impairs the fitness of neuroblastoma cell lines in a HIF2-dependent manner both ex vivo and in vivo. This fitness defect can be rescued by pVHL variants linked to paraganglioma, but not by pVHL variants associated with a low risk of paraganglioma. These findings suggest that HIF2 activity above a critical threshold prevents the development of paraganglioma.

 

Annals of Surgical Oncology

ASO Visual Abstract: Patient-Reported Outcomes 10 Years After Breast-Conserving Surgery for Early-Stage Breast Cancer

Dominici LS, Laws A, Lagendijk M, Grossmith S, Hughes M, Lin N, Mittendorf EA, King TA

 

Applied Immunohistochemistry and Molecular Morphology

Concordance of PD-L1 Expression in Metastatic Triple-negative Breast Cancer Between the 22C3 and E1L3N Antibodies Using Combined Positive Scoring

Erick TK, Lester SC, Garrido-Castro AC, Hughes M, Cunningham O, Lin NU, Mittendorf EA, Tolaney SM, Brock JE

 

Blood Advances

Intensive Induction Chemotherapy vs Hypomethylating Agents in Combination with Venetoclax in NPM1-Mutant AML

Shimony S, Liu Y, Schaefer EJ, Bystrom RP, Lindsley RC, Chen EC, DeAngelo DJ, Neuberg DS, Stone RM, Stahl M

 

Blood Advances

Myeloid Clonal Hematopoiesis of Indeterminate Potential in Patients with Chronic Lymphocytic Leukemia

Volpe VO, Sekar A, Santos Azevedo R, Mikhaleva M, Gibson CJ, Martindale SP, Fardoun R, Tyekucheva S PhD, Ren Y, Fernandes SM, Hahn CK, Getz G, Wu CJ, Davids MS, Brown JR

 

BMC Neurology

Exploring Clinical Markers of Axon Degeneration Processes in Chemotherapy-Induced Peripheral Neuropathy Among Young Adults Receiving Vincristine or Paclitaxel

Knoerl R, Mazzola E, Pazyra-Murphy M, Ryback B, Frazier AL, Freeman RL, Hammer M, LaCasce A, Ligibel J, Luskin MR, Segal RA

 
 

British Journal of Haematology

ERK1/2 Pro-Survival Signalling is Suppressed by Pirtobrutinib in Ibrutinib-Resistant MYD88-Mutated Lymphoma Cells

Munshi M, Liu X, Kofides A, Tsakmaklis N, Hunter ZR, Guerrera ML, Canning A, Gustine JN, Liu S, Hatcher JM, Chen J, Meid K, Sarosiek S, Flynn CA, Branagan AR, von Keudell G, Castillo JJ, Yang G, Treon SP

 

Cancer

Breastfeeding Experiences Among Young Breast Cancer Survivors: A Survey Study

Sella T, Sorouri K, Kirkner G, Snow C, Gelber SI, Peppercorn JM, Come SE, Partridge AH

 

Cancer Immunology Research

A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer

Huffman BM, Rahma OE, Tyan K, Li YY, Giobbie-Hurder A, Schlechter BL, Bockorny B, Manos MP, Cherniack AD, Baginska J, Mariño-Enríquez A, Kao KZ, Maloney AK, Ferro A, Kelland S, Ng K, Singh H, Welsh EL, Pfaff KL, Giannakis M, Rodig SJ, Hodi FS, Cleary JM

 
 

Cancer Research

Selective Enhancer Gain of Function Deregulates MYC Expression in Multiple Myeloma

Rahmat M, Alberge JB, Sklavenitis-Pistofidis R, Fulco CP, Heilpern-Mallory D, Dorfman D, Getz G, Pinello L, Ghobrial IM

 

Cell Chemical Biology

Small Molecules Targeting Selective PCK1 and PGC-1? Lysine Acetylation Cause Anti-Diabetic Action through Increased Lactate Oxidation

Mutlu B, Sharabi K, Sohn JH, Yuan B, Latorre-Muro P, Qin X, Yook JS, Yu D, Kajimura S, Hui S, Puigserver P

 

Clinical Cancer Research

Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer

Singh H, Kapner KS, Yuan C, Surana R, Huffman BM, Perez K, Cleary JM, Jordan AC, Dias Costa A, Williams HL, Raghavan S, Dougan SK, Nowak JA, Wolpin BM, Aguirre AJ

 

Cold Spring Harbor Perspectives in Medicine

Understanding the Warburg Effect in Cancer

Vander Heiden MG

 
 

Current Neurology and Neuroscience Reports

The Role of Mutant IDH Inhibitors in the Treatment of Glioma

Nakhate V, Lasica AB, Wen PY

 

Fertility and Sterility

Contraception Use and Changes in Young Women with Newly Diagnosed Breast Cancer

Tesch ME, Sorouri K, Zheng Y, Emmons KM, Dutton MC, Partridge AH

 

Frontier Oncology

Survival Outcomes in Patients with De Novo Metastatic Merkel Cell Carcinoma According to Site of Metastases

Khaddour K, Liu M, Kim EY, Bahar F, Lôbo MM, Giobbie-Hurder A, Silk AW, Thakuria M

 

Frontier Oncology

Testing Home-Based Exercise Strategies in Underserved Minority Cancer Patients Undergoing Chemotherapy (THRIVE) Trial: A Study Protocol

Gonzalo-Encabo P, Wilson RL, Christopher CN, Kang DW, Gardiner J, Perez M, Norris MK, Gundersen D, Freedman RA, Rebbeck TR, Dieli-Conwright CM

 

JCO Oncology Practice

Using Oncology Treatment Pathway Data to Evaluate Serious Illness Communication, Care Utilization, and End-of-Life Care for Patients with Cancer

Cotner CE, Tramontano AC, Post A, Finn B, Awan S, Gwynne N, Lindvall C, Tulsky JA, Jacobson JO, Jackman DM, Wright AA, Manz CR

 
 
 
 

Pediatric Quality and Safety

Outpatient Management of Fever and Neutropenia in Low-risk Children with Solid Tumors: A Quality Improvement Initiative

Bourgeois W, Paolino J, Garland R, Campbell K, Alvarez-Calderon F, Frazier AL, O'Neill AF, Ilowite M, Wong CI

 

Science Advances

Development of an Antigen-Based Approach to Noninvasively Image CAR T Cells in Real Time and as a Predictive Tool

Rowley J, Farid AS, Rakhshandehroo T, Allen H, Moravej H, Munaretto L, Codet E, Glockner H, Jacobson C, Rashidian M

 
 

Transplantation and Cellular Therapy

A Peer Support Intervention in Patients with Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation (HSCT): The STEPP Proof-of-Concept Trial

Amonoo HL, Guo M, Keane EP, Boardman AC, Song MT, Cutler C, Huffman JC, El-Jawahri A