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Dana-Farber Research News 10.15.2021

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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. 

October 15, 2021

Blood

Phase 1/2 Study of Uproleselan Added to Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia s

DeAngelo DJ

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 (NCT02306291) evaluated the safety, tolerability, and anti-leukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, 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]/complete response 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 aged 60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7+3). In these front-line 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‚Äëselectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML, and with high-risk cytogenetics and secondary AML in newly diagnosed older patients. In the R/R cohort, E‚Äëselectin expression above 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 strong rationale for phase 3 randomized confirmatory studies.


Cancer Discovery

An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Lin S, Scheidegger NK, Seong BKA, Kuljanin M, Wechsler CS, Kugener G, Robichaud AL, Saur Conway A, Mashaka T, Ryan JA, Mancias JD, Younger ST, Piccioni F, Letai A, Stegmaier K

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiological relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets.


Cancer Discovery

Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer

Jänne PA

HER3 is expressed in the majority of EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase 1, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated NSCLC with prior EGFR TKI therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg IV Q3W, the confirmed ORR by BICR (RECIST v1.1) was 39% (95% CI, 26.0-52.4), and median PFS was 8.2 (4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade {greater than or equal to}3 TEAE were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treating a broad range of drug-resistant cancers.


Cell

In-Vivo CRISPR Screens Identify the E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target

Wang X, Tokheim C, Gu SS, Wang B, Tang Q, Li Y, Traugh N, Zeng Z, Zhang Y, Li Z, Zhang B, Fu J, Xiao T, Li W, Meyer CA, Chu J, Jiang P, Cejas P, Lim K, Long H, Brown M, Liu XS

Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpd protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpd, which leads to polyubiquitination of C/ebpd. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpd to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment.


Gastroenterology

Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update

Duronio GN, Bala P, Spisak S, Sahgal P, Singh H, Zhang Y, Xie Y, Cejas P, Long HW, Bass AJ, Sethi NS

BACKGROUND AND AIMS: Genomic alterations that encourage stem cell activity and hinder proper maturation are central to the development of colorectal cancer (CRC). Key molecular mediators that promote these malignant properties require further elucidation to galvanize translational advances. We therefore aimed to characterize a key factor that blocks intestinal differentiation, define its transcriptional and epigenetic program, and provide preclinical evidence for therapeutic targeting in CRC.

METHODS: Intestinal tissue from transgenic mice and patients were analyzed by histopathology and immunostaining. Human CRC cells and neoplastic murine organoids were genetically manipulated for functional studies. Gene expression profiling was obtained through RNA sequencing. Histone modifications and transcription factor binding was determined by ChIP sequencing.

RESULTS: We demonstrate that SRY-box transcription factor 9 (SOX9) promotes CRC by activating a stem cell-like program that hinders intestinal differentiation. Intestinal adenomas and colorectal adenocarcinomas from mouse models and patients demonstrate ectopic and elevated expression of SOX9. Functional experiments indicate a requirement for SOX9 in human CRC cell lines and engineered neoplastic organoids. Disrupting SOX9 activity impairs primary CRC tumor growth by inducing intestinal differentiation. By binding to genome wide enhancers, SOX9 directly activates genes associated with Paneth and stem cell activity, including PROM1. SOX9 upregulates PROM1 via a WNT-responsive intronic enhancer. A pentaspan transmembrane protein, PROM1 utilizes its first intracellular domain to support stem cell signaling, at least in part through SOX9, reinforcing a PROM1-SOX9 positive feedback loop.

CONCLUSIONS: These studies establish SOX9 as a central regulator of an enhancer-driven stem cell-like program and carry important implications for developing therapeutics directed at overcoming differentiation defects in CRC.


Journal of Clinical Oncology

Checkpoint Blockade: Not Yet NINJA Status in Ovarian Cancer

Porter RL, Matulonis UA

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and although surgery and platinum-based chemotherapy effectively induce initial remission, most women will ultimately succumb to recurrent and therapy-resistant disease. High-grade serous histology is the most common EOC pathology and is molecularly characterized by defects in DNA repair, copy number alterations, microsatellite stable status, and low tumor mutational burden. Platinum-resistant ovarian cancer (PROC), defined as cancer that has progressed within 6 months of last platinum exposure, has a median overall survival (OS) of < 16 months, and new treatment strategies are exigently needed.


Journal of Clinical Oncology

Reply to G. Francolini et al

D'Amico AV, Xie W

We would like to thank Francolini et al for their interest in our study2 and thoughtful letter. Our study prospectively assessed the impact on both overall survival and radiation therapy (RT)–induced cancer incidence of adding docetaxel to RT and androgen deprivation therapy (ADT) in men with unfavorable-risk prostate cancer. Although overall survival was not prolonged among all men, there was a signal of possible benefit (hazard ratio [HR] 0.33) among men with a prostate-specific antigen < 4 ng/mL, which will be further explored in a meta-analysis using data compiled by the Intermediate Clinical Endpoints in Prostate Cancer (ICECaP) consortium. In addition, despite only nine RT-induced cancers, a significant reduction in these second cancers (age-adjusted HR, 0.13; 95% CI, 0.02 to 0.97) was observed in men randomly assigned to the docetaxel arm. The availability of oral docetaxel and its favorable toxicity profile provides an option for future study to minimize and possibly prevent the occurrence of RT-induced cancers.


New England Journal of Medicine

Phenotype, Specificity and Avidity of Antitumour CD8(+) T Cells in Melanoma

Jänne PA

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.
METHODS: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.
RESULTS: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.
CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).


Nature

Biologically Informed Deep Neural Network for Prostate Cancer Discovery

Elmarakeby HA, Arafeh R, Crowdis J, Gang S, Liu D, AlDubayan SH, Salari K, Richter C, Arnoff TE, Park J, Hahn WC, M Van Allen E

The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge. Recent advances in interpretability of machine learning models applied to biomedical problems may enable discovery and prediction in clinical cancer genomics. Here we developed P-NET-a biologically informed deep learning model-to stratify patients with prostate cancer by treatment-resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modelling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1, which were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.


Nature Communications

A Replication Stress Biomarker is Associated with Response to Gemcitabine Versus Combined Gemcitabine and ATR Inhibitor Therapy in Ovarian Cancer

Konstantinopoulos PA, Gulhan D, Lee EK, Cheng SC, Kochupurakkal B, Kolin DL, Liu JF, Stover EH, Curtis J, Tayob N, Polak M, Chowdhury D, Matulonis UA, D'Andrea AD, Shapiro GI

In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17-0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13-0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47-2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.


Nature Communications

Molecular Correlates of Response to Eribulin and Pembrolizumab in Hormone Receptor-Positive Metastatic Breast Cancer

Keenan TE, Guerriero JL, Barroso-Sousa R, Li T, O'Meara T, Giobbie-Hurder A, Tayob N, Hu J, Severgnini M, Agudo J, Anderson L, Attaya V, Park J, Conway J, He MX, Reardon B, Shannon E, Wulf G, Spring LM, Jeselsohn R, Krop I, Lin NU, Partridge A, Winer EP, Mittendorf EA, Liu D, Van Allen EM, Tolaney SM

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin‚ pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.


Nature Methods

Systematic Investigation of Cytokine Signaling Activity at the Tissue and Single-Cell Levels

Wucherpfennig KW

Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig; https://cytosig.ccr.cancer.gov ), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe coronavirus disease 2019.


Academic Radiology

MRI Changes in Breast Skin Following Preoperative Therapy for Patients with Inflammatory Breast Cancer

Yeh E, Nakhlis F, Bay C, Harrison BT, Bellon JR, Remolano MC, Jacene H, Giess C, Overmoyer B


American Journal of Kidney Diseases

Combined Nephrology and Palliative Medicine Fellowship Training: A Breath of Fresh AIRE

Gelfand SL


Blood Advances

Impact of Cryopreservation and Transit Times of Allogeneic Grafts on Hematopoietic and Immune Reconstitution

Maurer K, Kim HT, Kuczmarski TM, Garrity HM, Weber A, Reynolds CG, Liney D, Cutler CS, Antin JH, Koreth J, Ritz J, Shapiro RM, Romee R, Wu CJ, Soiffer RJ, Nikiforow S, Ho VT, Gooptu M


Blood Advances

Impact of Sickle Cell Trait on Morbidity and Mortality from SARS-CoV-2 Infection

Merz LE, Mistry K, Neuberg D, Freedman R, Menard G, Dorfman DM, Park HS, Jolley K, Achebe MO


Blood Advances

Integrated Safety Analysis of Umbralisib, a Dual PI3Kd/CK1e Inhibitor, in Relapsed/Refractory Lymphoid Malignancies

Davids MS


Blood Advances

Real-World Outcomes of Axicabtagene Ciloleucel in Adult Patients with Primary Mediastinal B-Cell Lymphoma

Crombie JL, Redd R, Saucier A, Jacobson CA, Armand P


Bone Marrow Transplantation

The Importance of Endothelial Protection: The Emerging Role of Defibrotide in Reversing Endothelial Injury and Its Sequelae

Richardson PG


Cancer Causes and Control

Correction To: Statins to Mitigate Cardiotoxicity in Cancer Patients Treated with Anthracyclines and/or Trastuzumab: A Systematic Review and Meta Analysis

Papatheodorou SI, Nohria A, Asnani A, Partridge AH


Cancer Immunology, Immunotherapy

Immune Cell Profiles in the Tumor Microenvironment of Early-Onset, Intermediate-Onset, and Later-Onset Colorectal Cancer

Ugai T, Väyrynen JP, Lau MC, Akimoto N, Väyrynen SA, Zhao M, Zhong R, Haruki K, Dias Costa A, Fujiyoshi K, Arima K, Wu K, Chan AT, Song M, Wang M, Lennerz JK, Ng K, Meyerhardt JA, Giannakis M, Nowak JA, Ogino S


Cancer Nursing

Stability of Symptom Clusters in Patients with Gynecologic Cancer Receiving Chemotherapy

Pozzar RA, Hammer MJ


Cancer Research

EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody Drug Conjugate HER3-DXd

Haikala HM, Lopez T, Köhler J, Eser PO, Xu M, Zeng Q, Teceno TJ, Ngo K, Zhao Y, Ivanova EV, Bertram AA, Leeper BA, Chambers ES, Adeni AE, Taus LJ, Kuraguchi M, Kirschmeier PT, Paweletz CP, Gokhale PC, Jänne PA


Current Neurology and Neuroscience Reports

Medical and Neurological Management of Brain Tumor Complications

Youssef G, Wen PY


European Journal of Cancer

Current Strategies for Intratumoural Immunotherapy - Beyond Immune Checkpoint Inhibition

Hodi FS


Haematologica

Cardiovascular Adverse Events in Patients with Chronic lymphocytic Leukemia Receiving Acalabrutinib Monotherapy: Pooled Analysis of 762 Patients

Brown JR


Haematologica

Randomized Controlled Trial of Geriatric Consultation Versus Standard Care in Older Adults with Hematologic Malignancies

DuMontier C, Uno H, Hshieh T, Zhou G, Chen R, Magnavita ES, Javedan H, Stone RM, Soiffer RJ, Driver JA, Abel GA


Journal of Clinical Investigation

RAF1 Amplification Drives a Subset of Bladder Tumors and Confers Sensitivity to MAPK-Directed Therapeutics

Bekele RT, Samant AS, Nassar AH, So J, Garcia EP, Curran CR, Hwang JH, Mayhew DL, Nag A, Thorner AR, Pan CX, Bellmunt J, Kwiatkowski DJ, Sonpavde GP, Van Allen EM, Mouw KW


Journal of Crohn’s and Colitis

Restored Macrophage Function Ameliorates Disease Pathophysiology in a Mouse Model for IL10 Receptor-deficient Very Early Onset Inflammatory Bowel Disease

Ackermann M, Mucci A, McCabe A, Frei S, Wright K, Snapper SB, Williams DA, Brendel C


Journal of Patient-Reported Outcomes

Measurement Properties of Brief Neuropathy Screening Items in Cancer Patients Receiving Taxanes, Platinums, or Proteasome Inhibitors

Knoerl R, Mazzola E, Salehi E, McCleary N, Ligibel JA, Reyes K


Journal of Thoracic Oncology

Axillary Lymphadenopathy After Coronavirus Disease 2019 Vaccinations in Patients with Thoracic Malignancy: Incidence, Predisposing Factors, and Imaging Characteristics

Nishino M, Hatabu H, Ricciuti B, Vaz V, Michael K, Awad MM


Journal of Pain and Symptom Management

Parent and Adolescent Perspectives on the Impact of COVID on the Care of Seriously Ill Children

Beight LJ, Helton G, Avery M, Dussel V, Wolfe J


Journal of Virology

Asymmetric Structures and Conformational Plasticity of the Uncleaved Full-Length Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Trimer/strong

Zhang S, Wang WL, Nguyen HT, Steinbock RT, Sodroski J, Mao Y