bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Myeloablative Haploidentical Transplantation Is Superior to Chemotherapy for Patients with Intermediate-risk Acute Myelogenous Leukemia in First Complete Remission
Authors: Lv Meng , Wang Yu , Chang Ying-Jun , Zhang Xiao-Hui , Xu Lan-Ping , Jiang Qian , Jiang Hao , Lu Jin , Chen Huan , Han Wei , Wang Feng-Rong , Wang Jing-Zhi , Chen Yao , Yan Chen-Hua , Zhang Yuan-Yuan , Sun Yu-Qian , Mo Xiao-Dong , Zhu Hong-Hu , Jia Jin-Song , Zhao Ting , Wang Jing , Liu Kai-Yan , Huang Xiao-Jun
Published: April 2023

AbstractPurpose:
Although myeloablative HLA haploidentical hematopoietic stem cell transplantation (haplo-HSCT) following pretransplant anti-thymocyte globulin (ATG) and granulocyte colony-stimulating factor (G-CSF) stimulated grafts (ATG+G-CSF) has been confirmed as an alternative to HSCT from HLA-matched sibling donors (MSD), the effect of haplo-HSCT on postremission treatment of patients with acute myeloid leukemia (AML) with intermediate risk (int-risk AML) who achieved first complete remission (CR1) has not been defined.
Patients and Methods:
In this prospective trial, among 443 consecutive patients ages 16–60 years with newly diagnosed de novo AML with int-risk cytogenetics, 147 patients with molecular int-risk AML who achieved CR1 within two courses of induction and remained in CR1 at 4 months postremission either received chemotherapy (n = 69) or underwent haplo-HSCT (n = 78).
Results:
The 3-year leukemia-free survival (LFS) and overall survival (OS) were significantly higher in the haplo-HSCT group than in the chemotherapy group (74.3% vs. 47.3%; P = 0.0004 and 80.8% vs. 53.5%; P = 0.0001, respectively). In the multivariate analysis with propensity score adjustment, postremission treatment (haplo-HSCT vs. chemotherapy) was an independent risk factor affecting the LFS [HR 0.360; 95% confidence interval (CI), 0.163–0.793; P = 0.011], OS (HR 0.361; 95% CI, 0.156–0.832; P = 0.017), and cumulative incidence of relapse (HR 0.161; 95% CI, 0.057–0.459; P = 0.001) either in entire cohort or stratified by minimal residual disease after the second consolidation.
Conclusions:
Myeloablative haplo-HSCT with ATG+G-CSF is superior to chemotherapy as a postremission treatment in patients with int-risk AML during CR1. Haplo-HSCT might be a first-line postremission therapy for int-risk AML in the absence of HLA-MSDs. Haplo-HSCT might be superior to chemotherapy as a first-line postremission treatment of intermediate-risk AML in CR1.
Data from A Validation Study on IDO Immune Biomarkers for Survival Prediction in Non–Small Cell Lung Cancer: Radiation Dose Fractionation Effect in Early-Stage Disease
Authors: Wang Weili , Huang Lei , Jin Jian-Yue , Pi Wenhu , Ellsworth Susannah G. , Jolly Shruti , Mellor Andrew L. , Machtay Mitchell , Kong Feng-Ming (Spring)
Published: April 2023

AbstractPurpose:
We recently reported that indoleamine 2, 3-dioxygenase (IDO) activity is significantly correlated with more distant metastasis and worse survival. The present study examined whether radiotherapy (RT) dose fractionation correlates with IDO-mediated immune activity in patients with early-stage NSCLC.

Methods: Patients with newly diagnosed stage I-II NSCLC treated with either conventionally fractionated 3-dimensional conformal radiotherapy (3DCRT) or stereotactic body radiotherapy (SBRT) were analyzed. Levels of two key molecules associated with the IDO immune checkpoint, serum kynurenine and the kynurenine:tryptophan ratio (K:T ratio), were measured at pre-RT, during-RT, and 3-month post-RT. The relationship between disease control outcomes [overall survival (OS), progression free survival, and local/regional/distant failure rates] and absolute levels of these markers, as well as dynamic changes in their levels during RT, was studied.
Results:
Fifty-six patients (SBRT = 28, 3DCRT = 28) with early-stage NSCLC were studied. In all patients, higher kynurenine post-RT was significantly associated with worse OS ([HR, 1.25; 95% confidence interval (CI), 1.01–1.55; P = 0.044). No statistically significant differences in absolute kynurenine levels or the K:T ratio were observed in patients treated with 3DCRT or SBRT at any of the three time points. However, the absolute kynurenine levels rose significantly more post-RT in the 3DCRT patients with a median increase 0.721 ng/mL, compared to that of SBRT patients (0.115 ng/mL); P = 0.022.
Conclusions:
This study validated that elevated IDO activity correlated with worse survival outcomes in patients with early-stage NSCLC treated with definitive RT. Hypofractionated SBRT may have less immunosuppressive effect than 3DCRT, as measured by IDO.
Data from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
Authors: Hai Josephine , Zhang Hua , Zhou Jin , Wu Zhong , Chen Ting , Papadopoulos Eleni , Dowling Catríona M. , Pyon Val , Pan Yuanwang , Liu Jie Bin , Bronson Roderick T. , Silver Heather , Lizotte Patrick H. , Deng Jiehui , Campbell Joshua D. , Sholl Lynette M. , Ng Christine , Tsao Ming-Sound , Thakurdin Cassandra , Bass Adam J. , Wong Kwok-Kin
Published: April 2023

AbstractPurpose:
Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed.
Experimental Design:
We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines.
Results:
We show that multiplex gene editing of mouse lung organoids using the CRISPR–Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell–mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti–PD-1 therapy.
Conclusions:
We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage–inducing therapies in the treatment of LSCC.
Data from BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells
Authors: Atay Cigdem , Kwak Taekyoung , Lavilla-Alonso Sergio , Donthireddy Laxminarasimha , Richards Allison , Moberg Valerie , Pilon-Thomas Shari , Schell Michael , Messina Jane L. , Rebecca Vito W. , Xiao Min , Tan Jiufeng , Zhang Gao , Weber Jeffrey S. , Herlyn Meenhard , Sarnaik Amod A. , Gabrilovich Dmitry I.
Published: April 2023

AbstractPurpose:
BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi.
Experimental Design:
Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT.
Results:
Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment.
Conclusions:
BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.

See related commentary by Goff and Rosenberg, p. 2682
Data from Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography
Authors: Greenwood Hannah E. , McCormick Patrick N. , Gendron Thibault , Glaser Matthias , Pereira Raul , Maddocks Oliver D. K. , Sander Kerstin , Zhang Tong , Koglin Norman , Lythgoe Mark F. , Årstad Erik , Hochhauser Daniel , Witney Timothy H.
Published: April 2023

AbstractPurpose:
Drug resistance is a major obstacle for the effective treatment of patients with high-grade serous ovarian cancer (HGSOC). Currently, there is no satisfactory way to identify patients with HGSOC that are refractive to the standard of care. Here, we propose the system xc− radiotracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate ([18F]FSPG) as a non-invasive method to measure upregulated antioxidant pathways present in drug-resistant HGSOC.
Experimental Design:
Using matched chemotherapy sensitive and resistant ovarian cancer cell lines, we assessed their antioxidant capacity and its relation to [18F]FSPG uptake, both in cells and in animal models of human ovarian cancer. We identified the mechanisms driving differential [18F]FSPG cell accumulation and evaluated [18F]FSPG tumor uptake as predictive marker of treatment response in drug-resistant tumors.
Results:
High intracellular glutathione (GSH) and low reactive oxygen species corresponded to decreased [18F]FSPG cell accumulation in drug-resistant versus drug-sensitive cells. Decreased [18F]FSPG uptake in drug-resistant cells was a consequence of changes in intracellular cystine, a key precursor in GSH biosynthesis. In vivo, [18F]FSPG uptake was decreased nearly 80% in chemotherapy-resistant A2780 tumors compared with parental drug-sensitive tumors, with nonresponding tumors displaying high levels of oxidized-to-reduced GSH. Treatment of drug-resistant A2780 tumors with doxorubicin resulted in no detectable change in tumor volume, GSH, or [18F]FSPG uptake.
Conclusions:
This study demonstrates the ability of [18F]FSPG to detect upregulated antioxidant pathways present in drug-resistant cancer. [18F]FSPG may therefore enable the identification of patients with HGSOC that are refractory to standard of care, allowing the transferal of drug-resistant patients to alternative therapies, thereby improving outcomes in this disease.
Data from Altered Gene Expression along the Glycolysis–Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer
Authors: Karasinska Joanna M. , Topham James T. , Kalloger Steve E. , Jang Gun Ho , Denroche Robert E. , Culibrk Luka , Williamson Laura M. , Wong Hui-Li , Lee Michael K.C. , O'Kane Grainne M. , Moore Richard A. , Mungall Andrew J. , Moore Malcolm J. , Warren Cassia , Metcalfe Andrew , Notta Faiyaz , Knox Jennifer J. , Gallinger Steven , Laskin Janessa , Marra Marco A. , Jones Steven J.M. , Renouf Daniel J. , Schaeffer David F.
Published: April 2023

AbstractPurpose:
Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis.
Experimental Design:
We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG).
Results:
On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes.
Conclusions:
Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.

See related commentary by Mehla and Singh, p. 6
Data from Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer
Authors: Croessmann Sarah , Formisano Luigi , Kinch Lisa N. , Gonzalez-Ericsson Paula I. , Sudhan Dhivya R. , Nagy Rebecca J. , Mathew Aju , Bernicker Eric H. , Cristofanilli Massimo , He Jie , Cutler Richard E. , Lalani Alshad S. , Miller Vincent A. , Lanman Richard B. , Grishin Nick V. , Arteaga Carlos L.
Published: April 2023

AbstractPurpose:
We examined the role of ERBB2-activating mutations in endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer.
Experimental Design:
ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ERBB2 mutations in ER+ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis was used to determine the molecular interaction of HERL755S with HER3. Small molecules and siRNAs were used to inhibit PI3Kα, TORC1, and HER3.
Results:
Genomic data revealed a higher rate of ERBB2 mutations in metastatic versus primary ER+ tumors. MCF7 cells with isogenically incorporated ERBB2 kinase domain mutations exhibited resistance to estrogen deprivation and to fulvestrant both in vitro and in vivo, despite maintaining inhibition of ERα transcriptional activity. Addition of the irreversible HER2 tyrosine kinase inhibitor neratinib restored sensitivity to fulvestrant. HER2-mutant MCF7 cells expressed higher levels of p-HER3, p-AKT, and p-S6 than cells with wild-type HER2. Structural analysis of the HER2L755S variant implicated a more flexible active state, potentially allowing for enhanced dimerization with HER3. Treatment with a PI3Kα inhibitor, a TORC1 inhibitor or HER3 siRNA, but not a MEK inhibitor, restored sensitivity to fulvestrant and to estrogen deprivation. Inhibition of mutant HER2 or TORC1, when combined with fulvestrant, equipotently inhibited growth of MCF7/ERBB2V777L xenografts, suggesting a role for TORC1 in antiestrogen resistance induced by ERBB2 mutations.
Conclusions:
ERBB2 mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to antiestrogen resistance in ER+ breast cancer. Dual blockade of the HER2 and ER pathways is required for the treatment of ER+/HER2 mutant breast cancers.
Data from Phase IB/II Study of Second-Line Therapy with Panitumumab, Irinotecan, and Everolimus (PIE) in KRAS Wild-Type Metastatic Colorectal Cancer
Authors: Townsend Amanda , Tebbutt Niall , Karapetis Christos , Cooper Pamela , Singhal Nimit , Yeend Susan , Pirc Louise , Joshi Rohit , Hardingham Jennifer , Price Timothy
Published: April 2023

Abstract
Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab, and everolimus.

Patients and Methods: Patients with KRAS exon 2 wild-type (WT) mCRC following failure of fluoropyrimidine-based therapy received i.v. irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14-day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using the Kaplan–Meier method, and results were analyzed as intention to treat. A preplanned exploratory biomarker analysis was performed.

Results: Forty-nine patients were enrolled. Dose level 1 (irinotecan 200 mg/m2, panitumumab 6 mg/kg, and everolimus 5 mg alternate day) was declared the MTD with no dose-limiting toxicities in six patients. Forty patients were treated at dose level 1: median age, 60 years (37–76); 65% male; 45% and 52.5%, respectively, with Eastern Cooperative Oncology Group values of 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhea (23%), mucositis (18%), rash (13%), fatigue (8%), dehydration (5%), neutropenia (20%), febrile neutropenia (8%), hypomagnesemia (20%), and hypokalemia (8%). Grade 4 toxicities were hypomagnesemia (5%) and neutropenia (3%). RR was 48%, and stable disease was 43%. Median progression-free survival (PFS) was 5.6 months, and median overall survival (OS) was 10.8 months. Twenty-five patients were RAS/RAF WT and had an RR of 60%, median PFS of 6.4 months, and OS of 11.8 months.

Conclusions: The toxicity of the panitumumab, irinotecan, and everolimus regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination. Clin Cancer Res; 24(16); 3838–44. ©2018 AACR.
Data from Mutational Analysis Identifies Therapeutic Biomarkers in Inflammatory Bowel Disease–Associated Colorectal Cancers
Authors: Din Shahida , Wong Kim , Mueller Mike F. , Oniscu Anca , Hewinson James , Black Catherine J. , Miller Martin L. , Jiménez-Sánchez Alejandro , Rabbie Roy , Rashid Mamunar , Satsangi Jack , Adams David J. , Arends Mark J.
Published: April 2023

Abstract
Purpose: Inflammatory bowel disease–associated colorectal cancers (IBD-CRC) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection, and treatment strategies. We aimed to identify biomarkers using whole-exome sequencing of IBD-CRCs to guide individualized management.

Experimental Design: Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined.

Results: Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but one of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA POLE. Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified six distinct mutation signatures in IBD-CRCs, three of which corresponded to known mechanisms of mutagenesis. Driver genes were also identified.

Conclusions: IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether IHC to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualize surveillance and treatment programs. Clin Cancer Res; 24(20); 5133–42. ©2018 AACR.
Data from ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy
Authors: Jaiswal Bijay S. , Durinck Steffen , Stawiski Eric W. , Yin Jianping , Wang Weiru , Lin Eva , Moffat John , Martin Scott E. , Modrusan Zora , Seshagiri Somasekar
Published: April 2023

Abstract
Purpose: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF- and/or RAS-mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS-mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance. However, as observed with other MAPK pathway inhibitors, treatment with ERK inhibitors is likely to cause resistance in the clinic. Here, we aimed to model the mechanism of resistance to ERK inhibitors.

Experimental Design: We tested five structurally different ATP-competitive ERK inhibitors representing three different scaffolds on BRAF/RAS-mutant cancer cell lines of different tissue types to generate resistant lines. We have used in vitro modeling, structural biology, and genomic analysis to understand the development of resistance to ERK inhibitors and the mechanisms leading to it.

Results: We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitors, ERBB receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK-inhibitor resistance.

Conclusions: These findings suggest that combination therapy with MEK or ERBB receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic. Clin Cancer Res; 24(16); 4044–55. ©2018 AACR.
Data from A Humanized Lym-1 CAR with Novel DAP10/DAP12 Signaling Domains Demonstrates Reduced Tonic Signaling and Increased Antitumor Activity in B-Cell Lymphoma Models
Authors: Zheng Long , Ren Luqing , Kouhi Aida , Khawli Leslie A. , Hu Peisheng , Kaslow Harvey R. , Epstein Alan L.
Published: April 2023

AbstractPurpose:
The murine Lym-1 mAb targets a discontinuous epitope (Lym-1 epitope) on several subtypes of HLA-DR, which is upregulated in a majority of human B-cell lymphomas and leukemias. Unlike CD19, the Lym-1 epitope does not downregulate upon crosslinking, which may provide an advantage as a target for CAR T-cell therapy. Lym-1 CAR T cells with a conventional 4-1BB and CD3ζ (BB3z) signaling domain exhibited impaired ex vivo expansion. This study aimed to identify the underlying mechanisms and develop strategies to overcome this effect.
Experimental Design:
A functional humanized Lym-1 antibody (huLym-1-B) was identified and its scFv form was used for CAR design. To overcome observed impaired expansion in vitro, a huLym-1-B CAR using DAP10 and DAP12 (DAP) signaling domains was evaluated for ex vivo expansion and in vivo function.
Results:
Impaired expansion in huLym-1-B-BB3z CAR T cells was shown to be due to ligand-dependent suboptimal CAR signaling caused by interaction of the CAR binding domain and the surface of human T cells. Using the novel DAP signaling domain construct, the effects of suboptimal CAR signaling were overcome to produce huLym-1-B CAR T cells with improved expansion ex vivo and function in vivo. In addition, the Lym-1 epitope does not significantly downregulate in response to huLym-1-B-DAP CAR T cells both ex vivo and in vivo.
Conclusions:
DAP intracellular domains can serve as signaling motifs for CAR, and this new construct enables nonimpaired production of huLym-1-B CAR T cells with potent in vivo antitumor efficacy.
Data from Evaluation of Novel Prostate-Specific Membrane Antigen-Targeted Near-Infrared Imaging Agent for Fluorescence-Guided Surgery of Prostate Cancer
Authors: Kularatne Sumith A. , Thomas Mini , Myers Carrie H. , Gagare Pravin , Kanduluru Ananda K. , Crian Christa J. , Cichocki Brandy N.
Published: April 2023

AbstractPurpose:
The ability to locate and remove all malignant lesions during radical prostatectomy leads not only to prevent biochemical recurrence (BCR) and possible side effects but also to improve the life expectancy of patients with prostate cancer. Fluorescence-guided surgery (FGS) has emerged as a technique that uses fluorescence to highlight cancerous cells and guide surgeons to resect tumors in real time. Thus, development of tumor-specific near-infrared (NIR) agents that target biomarkers solely expressed on prostate cancer cells will enable to assess negative tumor margins and affected lymph nodes.
Experimental Design:
Because PSMA is overexpressed in prostate cancer cells in >90% of the prostate cancer patient population, a prostate-specific membrane antigen (PSMA)-targeted NIR agent (OTL78) was designed and synthesized. Optical properties, in vitro and in vivo specificity, tumor-to-background ratio (TBR), accomplishment of negative surgical tumor margins using FGS, pharmacokinetics (PKs) properties, and preclinical toxicology of OTL78 were then evaluated in requisite models.
Results:
OTL78 binds to PSMA-expressing cells with high affinity, concentrates selectively to PSMA-positive cancer tissues, and clears rapidly from healthy tissues with a half-time of 17 minutes. It also exhibits an excellent TBR (5:1) as well as safety profile in animals.
Conclusions:
OTL78 is an excellent tumor-specific NIR agent for use in fluorescence-guided radical prostatectomy and FGS of other cancers.
Data from Biomarkers and Bone Imaging Dynamics Associated with Clinical Outcomes of Oral Cabozantinib Therapy in Metastatic Castrate-Resistant Prostate Cancer
Authors: Vaishampayan Ulka N. , Podgorski Izabela , Heilbrun Lance K. , Lawhorn-Crews Jawana M. , Dobson Kimberlee C. , Boerner Julie , Stark Karri , Smith Daryn W. , Heath Elisabeth I. , Fontana Joseph A. , Shields Anthony F.
Published: April 2023

AbstractPurpose:
Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.

Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0–2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured.
Results:
Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of −56% (range, −85 to −5%, n = 11) and −41% (range, −60 to −25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or <4 cycles, respectively. The FMAU PET demonstrated a median decline in SUVmax of −44% (−60 to −14%) and −42% (−63% to −23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit.
Conclusions:
Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.
Data from The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
Authors: Iglesias-Gato Diego , Thysell Elin , Tyanova Stefka , Crnalic Sead , Santos Alberto , Lima Thiago S. , Geiger Tamar , Cox Jürgen , Widmark Anders , Bergh Anders , Mann Matthias , Flores-Morales Amilcar , Wikström Pernilla
Published: April 2023

Abstract
Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.

Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.

Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid β-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair–related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.

Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433–44. ©2018 AACR.
Data from Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer
Authors: Tsujikawa Takahiro , Crocenzi Todd , Durham Jennifer N. , Sugar Elizabeth A. , Wu Annie A. , Onners Beth , Nauroth Julie M. , Anders Robert A. , Fertig Elana J. , Laheru Daniel A. , Reiss Kim , Vonderheide Robert H. , Ko Andrew H. , Tempero Margaret A. , Fisher George A. , Considine Michael , Danilova Ludmila , Brockstedt Dirk G. , Coussens Lisa M. , Jaffee Elizabeth M. , Le Dung T.
Published: April 2023

AbstractPurpose:
Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF–secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes–expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).
Patients and Methods:
Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates.
Results:
Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 [95% confidence interval (CI), 4.7–8.6] and 6.1 (95% CI, 3.5–7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55–1.34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35.3% vs. 11.9%) was manageable. Changes in the microenvironment, including increase in CD8+ T cells and a decrease in CD68+ myeloid cells, were observed in long-term survivors in Arm A only.
Conclusions:
Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.
Data from Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and Combination: A Meta-regression Analysis
Authors: Osipov Arsen , Lim Su Jin , Popovic Aleksandra , Azad Nilofer S. , Laheru Daniel A. , Zheng Lei , Jaffee Elizabeth M. , Wang Hao , Yarchoan Mark
Published: April 2023

AbstractPurpose:
Tumor mutational burden (TMB) has emerged as a potential predictive biomarker for clinical response to ICI therapy, but whether TMB also predicts toxicity remains unknown. We investigated the relationship between TMB, objective response rate (ORR), overall survival (OS), and toxicity for ICI therapy across multiple cancer types.
Experimental Design:
We searched MEDLINE, PubMed, and ASCO/ESMO/AACR meetings for clinical trials of anti-PD(L)1, CTLA-4, or combination in 29 cancer types. We assessed ICI administered, responses (complete or partial response), median OS, OS HR, and grade 3/4 toxicity. We conducted a systematic review, meta-analysis and meta-regression using tumor level TMB data from Foundation Medicine.
Results:
One hundred seventeen clinical trials, which included 12,450 patients treated with ICI therapy were analyzed. Meta-regression analysis revealed that TMB was significantly associated with ORR for anti-PD(L)1, anti–CTLA-4, and combination (P < 0.0001 for all), but not associated with toxicity in all treatment groups. OS data were unavailable for most studies included in our meta-analysis, and the relationship between TMB and OS in this subset was not significant (P = 0.26). In high TMB tumor types (≥10 mut/megabase) the improvement of ORR and increase in grade 3/4 toxicity with combination ICI therapy as compared with PD(L)1 monotherapy were 21.13% and 25.41%, respectively, as compared with 3.73% and 18.78% in low TMB tumor types (<10 mut/megabase).
Conclusions:
There is a positive association between TMB and clinical response with anti-PD(L)1, anti–CTLA-4, and combination ICIs, but no association between TMB and toxicity. These results imply a favorable risk/benefit ratio for ICIs in tumors with a higher TMB.
Data from Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors
Authors: Viitala Miro , Virtakoivu Reetta , Tadayon Sina , Rannikko Jenna , Jalkanen Sirpa , Hollmén Maija
Published: April 2023

AbstractPurpose:
As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and “reeducate” tumorigenic macrophages toward an immunostimulatory phenotype to activate the host's antitumor immunity.

Experimental Design: We investigated the role of the macrophage scavenger receptor common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) on tumor growth in multiple mouse cancer models with inflammatory and noninflammatory characteristics by using conditional knockouts, bone marrow chimeras, and cell depletion experiments. In addition, the efficacy of immunotherapeutic Clever-1 blockade as monotherapy or in combination with anti-PD-1 was tested.
Results:
Genetic deficiency of macrophage Clever-1 markedly impaired solid tumor growth. This effect was mediated by macrophages that became immunostimulatory in the absence of Clever-1, skewing the suppressive tumor microenvironment toward inflammation and activating endogenous antitumor CD8+ T cells. Comparable effects were achieved with immunotherapeutic blockade of Clever-1. Notably, these effects were similar to those achieved by PD-1 checkpoint inhibition. Moreover, combining anti-Clever-1 with anti-PD-1 provided synergistic benefit in aggressive, nonresponsive tumors.
Conclusions:
These findings demonstrate the importance of macrophages in mediating antitumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.

See related commentary by Mantovani and Bonecchi, p. 3202
Data from FDA Approval Summary: Mogamulizumab-kpkc for Mycosis Fungoides and Sézary Syndrome
Authors: Kasamon Yvette L. , Chen Haiyan , de Claro R. Angelo , Nie Lei , Ye Jingjing , Blumenthal Gideon M. , Farrell Ann T. , Pazdur Richard
Published: April 2023

Abstract
The FDA-approved mogamulizumab-kpkc, a CC chemokine receptor type 4 (CCR4)-directed mAb, in August 2018 for treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy. Regular approval was based on a randomized, open-label trial that randomized 372 such patients, with a median of 3 prior systemic therapies, to either mogamulizumab-kpkc or vorinostat. Investigator-assessed progression-free survival (PFS) was statistically significantly longer in the mogamulizumab-kpkc arm, which had an estimated median PFS of 7.6 months [95% confidence interval (CI), 5.6–10.2] compared with 3.1 months (95% CI, 2.8–4.0) in the vorinostat arm (HR = 0.53; 95% CI, 0.41–0.69). The confirmed overall response rate was 28% and 5%, respectively (P < 0.001), based on global composite response criteria. Adverse reactions occurring in at least 20% of mogamulizumab-kpkc recipients included rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infection. Serious adverse reactions occurred in 36% of patients, most often from infection. The prescribing information includes warnings for dermatologic toxicity, infusion reactions, infections, autoimmune complications, and complications of allogeneic hematopoietic stem cell transplantation, including severe and steroid-refractory graft-versus-host disease.

See related commentary by Larocca et al., p. 7272
Data from Safety, Efficacy, and Biomarker Analysis of Toripalimab in Previously Treated Advanced Melanoma: Results of the POLARIS-01 Multicenter Phase II Trial
Authors: Tang Bixia , Chi Zhihong , Chen Yingbo , Liu Xiufeng , Wu Di , Chen Jing , Song Xin , Wang Weifeng , Dong Lihou , Song Haifeng , Wu Hai , Feng Hui , Yao Sheng , Qin Shuikui , Zhang Xiaoshi , Guo Jun
Published: April 2023

AbstractPurpose:
In contrast to the predominant chronic UV exposure–induced cutaneous melanoma in Caucasians, acral and mucosal comprise the majority of melanomas in Asia and respond less effectively to established treatments. The clinical application of PD-1 blockade is yet to be explored in metastatic melanoma in China.
Patients and Methods:
This phase II study was to evaluate safety and efficacy of toripalimab in advanced Chinese patients with melanoma who had failed in systemic treatments. Toripalimab was given at 3 mg/kg i.v. once every 2 weeks until disease progression or unacceptable toxicity. The primary objective was safety and objective response rate.
Results:
128 Patients with melanoma were enrolled, including 50 acral and 22 mucosal. As of August 15, 2019, 23 months after the last enrollment, 116 (90.6%) experienced treatment-related adverse events. ≥Grade 3 TRAEs occurred in 25 (19.5%) patients. Among 127 patients assessed, 1 complete response, 21 partial response, and 51 stable disease were observed for objective response rate of 17.3% and disease control rate of 57.5%. Median duration of response was not reached. Median progression-free survival was 3.6 months [95% confidence interval (CI) 2.7–5.3] and median overall survival was 22.2 months (95% CI, 15.3–NE). Patients with positive PD-L1 staining in tumor biopsies had significant better ORR (38.5% vs. 11.9%, P = 0.0065), PFS (7.7 months vs. 2.7 months, P = 0.013), and OS (not reached vs. 14.4 months, P = 0.0005) than PD-L1–negative patients.
Conclusions:
This is the largest prospective anti-PD-1 clinical study in advanced melanoma with predominantly acral and mucosal subtypes. Toripalimab demonstrated a manageable safety profile and durable clinical response in Chinese patients with metastatic melanoma refractory to standard therapy.

See related commentary by Shoushtari et al., p. 4171
Data from A Radiomics Model for Predicting the Response to Bevacizumab in Brain Necrosis after Radiotherapy
Authors: Cai Jinhua , Zheng Junjiong , Shen Jun , Yuan Zhiyong , Xie Mingwei , Gao Miaomiao , Tan Hongqi , Liang Zhongguo , Rong Xiaoming , Li Yi , Li Honghong , Jiang Jingru , Zhao Huiying , Argyriou Andreas A. , Chua Melvin L.K. , Tang Yamei
Published: April 2023

AbstractPurpose:
Bevacizumab is considered a promising therapy for brain necrosis after radiotherapy, while some patients fail to derive benefit or even worsen. Hence, we developed and validated a radiomics model for predicting the response to bevacizumab in patients with brain necrosis after radiotherapy.
Experimental Design:
A total of 149 patients (with 194 brain lesions; 101, 51, and 42 in the training, internal, and external validation sets, respectively) receiving bevacizumab were enrolled. In total, 1,301 radiomic features were extracted from the pretreatment MRI images of each lesion. In the training set, a radiomics signature was constructed using the least absolute shrinkage and selection operator algorithm. Multivariable logistic regression analysis was then used to develop a radiomics model incorporated in the radiomics signature and independent clinical predictors. The performance of the model was assessed by its discrimination, calibration, and clinical usefulness with internal and external validation.
Results:
The radiomics signature consisted of 18 selected features and showed good discrimination performance. The model, which integrates the radiomics signature, the interval between radiotherapy and diagnosis of brain necrosis, and the interval between diagnosis of brain necrosis and treatment with bevacizumab, showed favorable calibration and discrimination in the training set (AUC 0.916). These findings were confirmed in the validation sets (AUC 0.912 and 0.827, respectively). Decision curve analysis confirmed the clinical utility of the model.
Conclusions:
The presented radiomics model, available as an online calculator, can serve as a user-friendly tool for individualized prediction of the response to bevacizumab in patients with brain necrosis after radiotherapy.
Data from Detection of Promoter DNA Methylation in Urine and Plasma Aids the Detection of Non–Small Cell Lung Cancer
Authors: Liu Bin , Ricarte Filho Julio , Mallisetty Apurva , Villani Cassandra , Kottorou Anastasia , Rodgers Kristen , Chen Chen , Ito Tomoaki , Holmes Kyla , Gastala Nicole , Valyi-Nagy Klara , David Odile , Gaba Ron C. , Ascoli Christian , Pasquinelli Mary , Feldman Lawrence E. , Massad Malek G. , Wang Tza-Huei , Jusue-Torres Ignacio , Benedetti Enrico , Winn Robert A. , Brock Malcolm V. , Herman James G. , Hulbert Alicia
Published: April 2023

AbstractPurpose:
Low-dose CT screening can reduce lung cancer–related mortality. However, CT screening has an FDR of nearly 96%. We sought to assess whether urine samples can be a source for DNA methylation–based detection of non–small cell lung cancer (NSCLC).
Experimental Design:
This nested case–control study of subjects with suspicious nodules on CT imaging obtained plasma and urine samples preoperatively. Cases (n = 74) had pathologic confirmation of NSCLC. Controls (n = 27) had a noncancer diagnosis. We detected promoter methylation in plasma and urine samples using methylation on beads and quantitative methylation–specific real-time PCR for cancer-specific genes (CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42).
Results:
DNA methylation at cancer-specific loci was detected in both plasma and urine, and was more frequent in patients with cancer compared with controls for all six genes in plasma and in CDO1, TAC1, HOXA9, and SOX17 in urine. Univariate and multivariate logistic regression analysis showed that methylation detection in each one of six genes in plasma and CDO1, TAC1, HOXA9, and SOX17 in urine were significantly associated with the diagnosis of NSCLC, independent of age, race, and smoking pack-years. When methylation was detected for three or more genes in both plasma and urine, the sensitivity and specificity for lung cancer diagnosis were 73% and 92%, respectively.
Conclusions:
DNA methylation–based biomarkers in plasma and urine could be useful as an adjunct to CT screening to guide decision-making regarding further invasive procedures in patients with pulmonary nodules.
Data from Targeting Extracellular Matrix Remodeling Restores BRAF Inhibitor Sensitivity in BRAFi-resistant Melanoma
Authors: Marusak Charles , Thakur Varsha , Li Yuan , Freitas Juliano T. , Zmina Patrick M. , Thakur Vijay S. , Chang Mayland , Gao Ming , Tan Jiufeng , Xiao Min , Lu Yiling , Mills Gordon B. , Flaherty Keith , Frederick Dennie T. , Miao Benchun , Sullivan Ryan J. , Moll Tabea , Boland Genevieve M. , Herlyn Meenhard , Zhang Gao , Bedogni Barbara
Published: April 2023

AbstractPurpose:
The extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy.
Experimental Design:
Publicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma in patients, patient-derived xenografts, and cell line–derived tumors. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP, inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322, or overexpression of MT1-MMP was used to assess the role of MT1-MMP in mediating resistance to BRAFi.
Results:
MT1-MMP was consistently upregulated in posttreatment tumor samples derived from patients upon disease progression and in melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA- or ND322-mediated inhibition of MT1-MMP synergized with BRAFi leading to resensitization of resistant cells and tumors to BRAFi. The resistant phenotype depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP uncleavable matrixes were resensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinβ1 (ITGB1)/FAK signaling, as restoration of ITGB1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFβ dependent, as inhibition of TGFβ receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition.
Conclusions:
BRAF inhibition results in a selective pressure toward higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.