Blood
A 3-Pronged Attack on TP53-Mutated MCL
Ryan CE, LaCasce AS
In this issue of Blood, Kumar and colleagues report results from, to our knowledge, the first study conducted in mantle cell lymphoma (MCL) specifically for patients with TP53-mutated disease. The highly promising results lay the foundation for a new treatment approach. Effective treatment of TP53-mutated MCL has been a long-standing challenge in the field. Analysis of outcomes in the Nordic MCL2 and MCL3 trials, which investigated cytarabine-containing chemoimmunotherapy induction followed by consolidative autologous stem cell transplantation, first highlighted the dismal outcomes for such patients. The median overall survival (OS) was 1.8 years vs 12.7 years for patients with and without TP53-mutated disease, respectively. At present there is no clear effective standard-of-care (SOC) treatment for patients with TP53-mutated MCL, and new frontline approaches are needed.
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Blood
Development of Hyperdiploidy Starts at an Early Age and Takes a Decade to Complete
Samur MK, Aktas Samur A, Shah P, Park JS, Fulciniti M, Shammas M, Anderson KC, Parmigiani G, Munshi NC
Nearly half of patients with multiple myeloma (MM) have hyperdiploidy (HMM) at diagnosis. Although HMM occurs early, the mutational processes before and after hyperdiploidy are still unclear. Here, we used 72 whole-genome sequencing samples from patients with HMM and identified pre- and post-HMM mutations to define the chronology of the development of hyperdiploidy. An MM cell accumulated a median of 0.56 mutations per megabase before HMM, and for every clonal pre-HMM mutation, 1.21 mutations per megabase accumulated after HMM. This analysis using mutations before and after hyperdiploidy shows that hyperdiploidy happens after somatic hypermutation. Prehyperdiploidy mutations are activation-induced cytidine deaminase and age/clock-like signature driven, whereas posthyperdiploidy mutations are from DNA damage and APOBEC. Interestingly, the first hyperdiploidy event occurred within the first 3 decades of life and took a decade to complete. Copy number changes affecting chromosomes 15 and 19 occurred first. Finally, mutations before initiating event affected chromosomes at different rates, whereas post-initiating event mutational processes affect each chromosome equally.
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Blood
Is it Time to Screen for Multiple Myeloma?
Ghobrial IM, Chabrun F
In this issue, Visram et al make a significant advancement in the controversy of screening of multiple myeloma (MM) by providing an initial answer to the question “Is monoclonal gammopathy the same entity when diagnosed through screening compared with incidental detection?” The study addresses this concern, demonstrating that after accounting for competing risks of death, the progression risk is similar for patients with screened vs clinically detected monoclonal gammopathy of undetermined significance (MGUS). They also found that progression risk factors, such as the size of the M spike, abnormal free light chain ratio, and immunoparesis, are consistent regardless of how MGUS is detected.
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Journal of Clinical Oncology
Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study
Sands J
PURPOSE: The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC).
METHODS: Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m2 once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points.
RESULTS: In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ?3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively.
CONCLUSION: Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.
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Journal of Clinical Oncology
First-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients with EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer in the Phase III EXCLAIM-2 Trial
Jänne PA
PURPOSE: Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets EGFR exon 20 insertion (ex20ins) mutations in non-small cell lung cancer (NSCLC). This open-label, phase III trial (EXCLAIM-2: ClinicalTrials.gov identifier: NCT04129502) compared mobocertinib versus platinum-based chemotherapy as first-line treatment of EGFR ex20ins+ advanced/metastatic NSCLC.
METHODS: Patients with treatment-naive EGFR ex20ins+ locally advanced/metastatic NSCLC were randomly assigned 1:1 to mobocertinib 160 mg once daily or pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by maintenance pemetrexed. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR), with planned interim analysis (IA) after approximately 70% of 227 expected PFS events.
RESULTS: A total of 354 patients were randomly assigned (mobocertinib: n = 179; chemotherapy: n = 175). Baseline characteristics were balanced between arms. At IA (cutoff: April 4, 2023), the median PFS per BICR was 9.6 months in each treatment arm (hazard ratio [HR], 1.04 [95% CI, 0.77 to 1.39]; P = .803). The primary end point crossed the prespecified futility boundary (HR > 1). The confirmed objective response rate (95% CI) per BICR was 32% (26 to 40) with mobocertinib versus 30% (24 to 38) with chemotherapy; the median duration of response was 12.0 versus 8.4 months. Quality-of-life assessments indicated clinically meaningful delays in time to deterioration of lung cancer symptoms, cognitive function, and constipation with mobocertinib versus chemotherapy. Grade ?3 adverse events in >5% of patients (mobocertinib, chemotherapy) were diarrhea (20%, 1%), anemia (6%, 10%), increased lipase (6%, 0%), and decreased neutrophil count (1%, 7%).
CONCLUSION: The EXCLAIM-2 trial did not meet its primary end point. The efficacy of mobocertinib was not superior to platinum-based chemotherapy for first-line treatment of patients with EGFR ex20ins+ advanced/metastatic NSCLC.
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Journal of Clinical Oncology
Timely Reporting of Patient-Reported Outcomes in Cancer Clinical Trials: An Ethical Imperative
Blackstone EC, Meyerhardt JA, Abel GA
Cancer treatment often involves significant toxicity and interruptions to daily life. As a result, patient-reported outcomes (PROs) such as health-related quality of life (HRQoL) are an essential component of cancer research as they provide critical insights into the effects of therapies for patients beyond disease response and survival outcomes. Many clinical trials measure symptoms only (eg, pain) more so than a full suite of HRQoL domains. By contrast, HRQoL encompasses physical, psychological, and social impacts of treatment, augmenting symptoms and adverse events recovered by study teams and amplifying patient voices in cancer research. The hope is that patients' sacrifices in HRQoL are worthwhile to maximize chance of cure or disease control, but weighing these considerations is impossible without treatment-aligned HRQoL data available to inform decision making. Incorporating PROs is particularly important in the context of increasing reliance on surrogate outcomes such as progression-free survival (PFS) in cancer trials. If a new treatment is approved on the basis of surrogate measures alone, there is no way of knowing what those outcomes mean for the day-to-day lived experiences of patients. For these reasons, collection and timely publication of PROs are necessary—and indeed an ethical imperative—for holistic evaluation of new cancer therapies in clinical trials. Although valuable progress has been made in incorporating PRO collection into cancer trials, inadequate reporting of results combined with increasing use of surrogates threatens both scientific validity and ethical conduct of cancer trials. Recommendations are provided to researchers, journal editors, and regulators to ensure that PRO data are available for new cancer therapies going forward.
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Molecular Cell
A Methyltransferase-Independent Role for METTL1 in tRNA Aminoacylation and Oncogenic Transformation
Ali RH, Orellana EA, Lee SH, Chae YC, Chen Y, Kennedy AL, Gutierrez AE, Papke DJ, Valenzuela M, Silverman B, Ficarro SB, Marto JA, Fletcher CDM, Perez-Atayde A, Alcindor T, Shimamura A, Prensner JR, Gregory RI, Gutierrez A
Amplification of chromosomal material derived from 12q13-15 is common in human cancer and believed to result in overexpression of multiple collaborating oncogenes. To define the oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase METTL1. This was surprising, because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases and promotes tRNA aminoacylation, polysome formation, and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. We propose that METTL1 overexpression promotes sarcomagenesis by stimulating tRNA aminoacylation, protein synthesis, and tumor cell growth independent of its methyltransferase activity.
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Nature
CD45-PET is a Robust, Non-Invasive Tool for Imaging Inflammation
Salehi Farid A, Rowley JE, Allen HH, Kruger IG, Tavakolpour S, Neeley K, Cong M, Shahbazian H, Dorafshani N, Berrada A, MacDonagh AC, Padera RF, Brugarolas P, Packard AB, Rosenbaum MW, Divakaran S, Di Carli MF, Rashidian M
Imaging inflammation holds immense potential for advancing the diagnosis, treatment and prognosis of many conditions1-3. The lack of a specific and sensitive positron emission tomography (PET) probe to detect inflammation is a critical challenge. To bridge this gap, we present CD45-PET imaging, which detects inflammation with exceptional sensitivity and clarity in several preclinical models. Notably, the intensity of the CD45-PET signal correlates robustly with the severity of disease in models of inflammatory lung and bowel diseases, outperforming 18F-fluorodeoxyglucose PET, the most widely used imaging modality for inflammation globally. Longitudinal CD45-PET imaging further enables precise monitoring of dynamic changes in tissue-specific inflammatory profiles. Finally, we developed a human CD45-PET probe for clinical translation that effectively detects human immune cells in a humanized mouse model. CD45-PET imaging holds substantial clinical promise, offering a tool for guiding diagnostic and therapeutic decisions for inflammatory diseases through a precise, whole-body assessment of the inflammation profiles of individual patients.
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Nature Cancer
Selective Deficiency of Mitochondrial Respiratory Complex I Subunits Ndufs4/6 Causes Tumor Immunogenicity
Liang J, Vitale T, Zhang X, Jackson TD, Yu D, Jedrychowski M, Gygi SP, Widlund HR, Wucherpfennig KW, Puigserver P
Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.
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Nature Communications
A Compendium of Amplification-Related Gain of Sensitivity Genes in Human Cancer
Rendo V, Khuu N, Huang K, Swift M, He Y, Bandopadhayay P, Moody S, Seo JH, Stover EH, Garraway L, Hahn WC, Stegmaier K, Chowdhury D, Beroukhim R
While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on "bystander" genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8,000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed. Combining these approaches, we propose a class of 'Amplification-Related Gain Of Sensitivity' (ARGOS) genes located in commonly amplified regions, yet expressed at lower levels than expected by their copy number, and toxic when overexpressed. We validate RBM14 as an ARGOS gene in lung and breast cancer cells, and suggest a toxicity mechanism involving altered DNA damage response and STING signaling. We additionally observe increased patient survival in a radiation-treated cancer cohort with RBM14 amplification.
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Science Immunology
Coordinated Immune Networks in Leukemia Bone Marrow Microenvironments Distinguish Response to Cellular Therapy
Maurer K, Borji M, Penter L, Brenner JR, Southard J, Krishna S, Lu W, Lyu H, Abbondanza D, Mangum C, Neuberg DS, Farhi SL, Li S, Livak KJ, Ritz J, Soiffer RJ, Wu CJ
Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded ZNF683+ CD8+ cytotoxic T lymphocytes with in vitro specificity for patient-matched AML. These cells originated primarily from the DLI product and appeared to coordinate antitumor immune responses through interaction with diverse immune cell types within the marrow microenvironment. Nonresponders lacked this cross-talk and had cytotoxic T lymphocytes with elevated TIGIT expression. Our study identifies recipient bone marrow microenvironment differences as a determinant of an effective antileukemia response and opens opportunities to modulate cellular therapy.
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Clinical Cancer Research
Re-Irradiation Plus Pembrolizumab: A Phase II Study for Patients with Recurrent Glioblastoma
Tanguturi SK, Nayak L, Wong ET, Hertan LM, McCluskey C, Hayden J, Muzikansky A, Nakhawa S, Japo J, Bossi CC, Meylan M, Tian Y, Barlow GL, Speliakos P, Ayoub G, Meredith DM, Ligon KL, Haas-Kogan D, Huang K, Wucherpfennig KW, Wen PY, Reardon DA
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