tbuckley/cabot-search huggingface dataset:
Characterization of diverse targetable <i>ERBB2</i> alterations in 512,993 patients with solid tumors.
Authors: Dazhi Liu, Rachel B Keller-Evans, Alexa B. Schrock, Alexander E. Drilon, Justin Jee, Bob T. Li
Journal: Journal of Clinical Oncology (2024)

3129 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated activity against a range of HER2-expressing and HER2-mutant (mut) solid tumors. We present an extensive landscape of ERBB2 alterations (alt) that may predict sensitivity to HER2-targeted therapies in development with a focus on mutations and cancer types without approved indications. Methods: We queried institutional databases (MSKCC and Foundation Medicine, Inc.) of comprehensive genomic profiling (CGP) performed on solid tumor tissue samples using either MSK-IMPACT (N=83,332; MSK) or FoundationOne/FoundationOne CDx (N=429,661; FMI) and on patient-matched liquid biopsies using FoundationOne Liquid CDx (N=1,922). ctDNA tumor fraction (ctDNA TF) on FoundationOne Liquid CDx was estimated using a composite algorithm. Clinicopathological characteristics and treatment outcomes were annotated for MSK-IMPACT samples. Results: ERBB2 activating alt were detected in 6.6% (n=28,508) and 5.0% (n=4,133) of tumors in the FMI and MSK cohorts, respectively. In FMI tissue samples, ERBB2 alt were most prevalent in gastroesophageal (GEC; 18.1%), bladder (18.0%), salivary gland (14.1%), breast (12.7%), and uterine (12.1%) cancers. The cancer types with the largest number of ERBB2mut tumors, specifically, included NSCLC (n=1,618, 1.9%), breast (n=1,565, 3.5%), colorectal (CRC; n=1,221, 2.3%), bladder (n=855, 8.8%), and GEC (n=660, 3.4%). Across these 5 cancers, ERBB2 mut were most commonly located in the kinase domain (KD; 58%), followed by the extracellular domain (ECD; 28%) and transmembrane domain (TMD; 2%). Rare splice site mut and in-frame deletions resulting in exon 16 loss (Ex16Alt) were also observed (n=76, &lt;0.1%). ERBB2 mut were found to be mutually exclusive with other RTK/MAPK driver oncogenes including: EGFR, KRAS, ALK, MET, BRAF, and RET in NSCLC; FGFR1 in breast cancer; BRAF in CRC; and FGFR3 in bladder cancer. In patient-matched liquid biopsy samples, sensitivity for detecting ERBB2 amplifications (amp; 33.3%, 43/129) was lower than for detecting ERBB2 mut (72.3%, 47/65) across select cancers. However, sensitivity for detection of both alts was improved in liquid samples with elevated ctDNA TF (≥1%), increasing to 52.6% (40/76) for amp and 97.3% (36/37) for mut. In the MSK cohort, 110 of 986 (11.2%) patients with ERBB2 mut non-NSCLC tumors received one or more HER2-targeted therapies, including ADCs. Clinical responses to HER2-targeted therapies were observed in patients harboring KD mut (n=10), ECD mut (n=6), TMD mut (V659E, n=1), and in 1 patient with a V697L mut. Conclusions: CGP detects diverse ERBB2activating alt at a high incidence in solid tumor types beyond NSCLC. These represent patient populations who may benefit from HER2-directed therapies. Trials of novel HER2-targeted agents are necessary to refine our understanding of the biological dependency of HER2 alterations.
The genomic, transcriptomic, and immunologic landscape of TEM8 (<i>ANTXR1</i>) in small-cell lung cancer (SCLC).
Authors: Samuel A. Kareff, Harris Benjamin Krause, Andrew Elliott, Gilberto Lopes, Emil Lou, Heloisa P. Soares, Matthew James Oberley, Aman Chauhan
Journal: Journal of Clinical Oncology (2024)

3128 Background: The TEM8 receptor (coded by ANTXR1) plays several roles in oncogenesis. Novel oncolytic therapies, such as the SVV-01 virus, uniquely bind this protein in tumor histologies such as small-cell lung cancer (SCLC). Emerging pre-clinical data suggest that TEM8-targeting therapies may convert immunologically “cold” tumor microenvironments (TME) into “hot” milieu with greater responses to immune checkpoint inhibitors (ICIs). Methods: NextGen sequencing of DNA (592 genes or whole exome)/RNA (whole transcriptome) was performed on SCLC ( N=1404) submitted to Caris Life Sciences (Phoenix, AZ). Mutations were defined as pathogenic SNVs/indels. ANTXR1 H and ANTXR1 L samples included those with &gt;75 th and &lt;25 th percentile expression, respectively. PD-L1 expression (22c3; Positive (+):TPS ³1%) was assessed by IHC. High tumor mutational burden (TMB-H) was defined as ≥10 mutations per MB. Cell infiltration in the TME was estimated by QuantiSEQ. Gene expression profiles were analyzed for transcriptional signatures predictive of response to immunotherapy (T cell-inflamed) and MAPK pathway activation score (MPAS). Real-world median overall survival (mOS) was assessed from insurance claims data, and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients. Mann-Whitney U and X 2 /Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( p&lt;0.05). Results: No pathogenic mutations were significantly associated with ANTXR1 H vs L tumors ( p&gt;0.05 for all), along with no differences in the prevalence of TMB-H (28.6% vs 36.3%, p=1) or PDL1+ (45.0%: vs 35.0%, p=1). However, a greater proportion of B cells (6.53 % vs 5.12%, p&lt;0.001), M1 (1.63% vs 0.37%, p&lt;0.001) and M2 macrophages (3.40% vs 1.50%, p&lt;0.001) were observed in ANTXR1 H TME, which were more frequently classified as T cell-inflamed compared to ANTXR1 L TME (23% vs 5%, p&lt;0.001). ANTXR1 H tumors also had higher MPAS compared to ANTXR1 L (1.36 vs -1.86 arbitrary units, p&lt;0.001). There was no significant difference in mOS between ANTXR1 H vs L tumors (12.2 vs 10.5 months, HR: 0.95, p=0.678). Conclusions: Increased B cell, M1 and M2 macrophage infiltrates, and increased prevalence of T-cell inflamed tumors in ANTXR1 H TME suggest that these patients with SCLC may respond preferentially to ICI. A Phase 1 trial incorporating SVV-01 along with ICI is underway. Prospective investigation of molecular associations and clinical outcomes related to ANTXR1 expression in SCLC is warranted.
PAS-004: A novel macrocyclic MEK inhibitor to inhibit cancer cell growth in vitro and tumor growth in mouse xenograft studies.
Authors: Graeme Currie, Michael Leviten, Lisa Ryner, Uday Khire, Mathew Lazarus
Journal: Journal of Clinical Oncology (2024)

3126 Background: Three MEK inhibitors have been approved to date to treat melanomas driven by RAS pathway mutations and a 4 th compound (selumetinib) is approved to treat Neurofibromatosis type 1 (NF1) in pediatric patients. PAS-004 is the first macrocyclic MEK inhibitor in development for solid tumors and NF1. Methods: Ten NRAS mutant cancer cell lines were cultured for 48 hrs in the presence of the MEK inhibitor PAS-004, trametinib, binimetinib (bini) and selumetinib (selu) and cell proliferation was assayed using a Cell Titer Glo luminescence assay. The anti-tumor activity of PAS-004 was compared with selu and bini in two mouse xenograft studies using NRAS mutant human hepatocellular carcinoma (HCC) and lung carcinoma cell lines. Dose response was assessed with treatment initiated when the tumor reached a volume of 150 mm 3 and mice treated for 20 days. Body weights and tumor volumes were measured twice weekly. Tumors were excised at the end of the study and pERK inhibition was assessed by Western blot. Terminal plasma was collected for PK analysis. Results: PAS-004 strongly inhibited 5/10 NRAS mutant cancer lines with IC 50 values ranging from 0.024 to 0.306 µM. Maximal growth inhibition of &gt;50% was achieved by PAS-004 in 8 cell lines and PAS-004 achieved greater maximal inhibition in 7/10 lines vs selu and bini. PAS-004 inhibition was comparable to trametinib in 5/10 cell lines tested. However, in contrast to trametinib PAS-004 did not reach a plateau at the highest dose tested in three of these lines. In the HCC xenograft study the highest dose of PAS-004 completely prevented tumor growth and the same dose caused a 69% reduction in tumor volume in the lung carcinoma xenograft study. The anti-tumor efficacy of PAS-004, when taken at equivalent doses, was shown to be superior to that of bini and selu. Specifically, PAS-004 at dose levels of 10 mg/kg and 5 mg/kg, once daily, exhibited higher efficacy compared to bini and selu at dose levels of 5 mg/kg and 2.5 mg/kg, when administered twice daily, respectively. No significant differences in body weight loss were seen between the compounds. Conclusions: The novel macrocyclic MEK inhibitorPAS-004 inhibited NRAS mutant tumor growth in mouse xenograft studies with similar activity as the approved MEK inhibitors selu and bini. In vitro, PAS-004 provided greater maximal growth inhibition of NRAS lines than selu and bini. These results support investigating PAS-004 further and a clinical trial in patients with advanced solid tumors carrying RAS pathway mutations, including NRAS variants, is ongoing.
Fly Me to the Micron: Microtechnologies for Drosophila Research
Authors: Utku M. Sonmez, Nolan Frey, Philip R. LeDuc, Jonathan S. Minden
Journal: Annual Review of Biomedical Engineering (2024)

Multicellular model organisms, such as Drosophila melanogaster (fruit fly), are frequently used in a myriad of biological research studies due to their biological significance and global standardization. However, traditional tools used in these studies generally require manual handling, subjective phenotyping, and bulk treatment of the organisms, resulting in laborious experimental protocols with limited accuracy. Advancements in microtechnology over the course of the last two decades have allowed researchers to develop automated, high-throughput, and multifunctional experimental tools that enable novel experimental paradigms that would not be possible otherwise. We discuss recent advances in microtechnological systems developed for small model organisms using D. melanogaster as an example. We critically analyze the state of the field by comparing the systems produced for different applications. Additionally, we suggest design guidelines, operational tips, and new research directions based on the technical and knowledge gaps in the literature. This review aims to foster interdisciplinary work by helping engineers to familiarize themselves with model organisms while presenting the most recent advances in microengineering strategies to biologists.
Multi-ethnic genome-wide association study to identify a novel locus for susceptibility to immune-related adverse events from immune checkpoint inhibitors.
Authors: Yiqing Huang, Joseph J Zhao, Alvin Wong, Sen Hee Tay, Yvonne Li'en Ang, Boon Cher Goh, Ross A. Soo, Folefac Aminkeng
Journal: Journal of Clinical Oncology (2024)

3090 Background: Immune-related adverse events (IrAEs) arising from immune checkpoint inhibitors (ICIs) can be unpredictable. As genomic variation underlies both disease susceptibility and drug responses, genomic markers may predict for the development of IrAEs. We perform a pioneering pharmacogenomic study across a multi-ethnic Asian patient population to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: From March 2018 – July 2023, cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital were recruited. IrAEs were characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed by SVS/HelixTree, PLINK and R. Genetic association was performed by logistic regression (additive model), accounting for all possible confounding factors. Bonferroni corrected P &lt; 1.28E-07 (0.05/390,925 SNPs passed QC) was considered statistically significant. Results: Genome-wide association study (GWAS) was conducted amongst 507 patients of Asian Ancestry (Chinese, Malay, Indian and Others). Median age was 63. Majority were male (66.5%), Chinese (76.7%), ECOG PS 0-1 (40.1%) and had stage IV cancer at diagnosis (67.2%). Non-small cell lung cancer (37.1%), renal cell carcinoma (12.2%) and hepatocellular carcinoma (7.7%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, durvalumab and atezolizumab, respectively (47.1%, 23.9%, 12.5%, 11.3%). 0.8% of patients received dual ICIs concurrently. Median duration of treatment was 142 days and median follow-up was 147 days. IrAEs were seen in 43.7% of patients. Skin (24.1%), endocrine (8.1%) and hepatotoxicity (6.1%) were the most common IrAEs. 4.9% of patients had grade ≥3 toxicity, of which skin (3.6%), hepatotoxicity (3.0%) and pulmonary toxicity (1.8%) were the most common. Multi-ethnic GWAS analysis identified one potential novel genetic locus associated with CTCAE grade ≥3 IrAEs. chr3:163402331 rs146525069; P = 7.29E-08, OR (95%CI) = 17.08 (5.40- 54.04); minor allele = A, 10.91% in Cases vs 0.71% in Controls. Conclusions: This pharmacogenomics GWAS uncovered a novel locus for susceptibility to serious immune-related adverse events from immune checkpoint inhibitors. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing. Our study provides a potential biological mechanism for IrAEs and a step towards more effective clinical translation of pharmacogenetic testing to personalize ICI use.
BY101921: Restoring interferon signaling and anti-tumor immunity through PARP7 inhibition.
Authors: Jinming Yu, Yuping Sun, Yonggang Wei, Fei Ye, Yuqin Zhu, Yang Chen, Rui Liu
Journal: Journal of Clinical Oncology (2024)

3123 Background: PARP7( TIPARP), a member of monoPARP family, catalyzes ADP-ribose transfer to specific amino acids within itself and other substrate proteins, utilizing nicotinamide adenine dinucleotide (NAD + ) as substrate. It plays a vital role in various biological processes such as gene expression, protein degradation, and cellular stress response. PARP7 amplification has been observed in various cancers, including squamous cell carcinoma, ovarian cancer, breast cancer, and pancreatic ductal adenocarcinoma. Over expression of PARP7 correlates with reduced survival in squamous cell carcinoma. PARP7's MARylation of α-tubulin induces microtubule instability, promoting proliferation and migration of ovarian cancer cells. As a negative regulator of tumor cell nucleic acid sensing, PARP7 inhibits TBK1 through. This, in turn, hampers the cGAS-STING signal pathway and downregulates the type Ⅰ interferon expression. BY101921, developed by Chengdu Baiyu Pharmaceutical, is a highly selective PARP7 inhibitor demonstrating significant anti-tumor effect in vitro and in vivo, both alone and in combination with anti-PD-1. Methods: Enzymatic evaluation was conducted on BY101921 to assess its selectivity among major PARP family members. PK studies were investigated in both mouse and dog species. The anti-tumor activity of BY101921, both as a monotherapy and in combo with anti-PD-1, was investigated in NCI-H1373 and CT26 tumor-bearing mice, respectively. In terms of anti-tumor mechanism, pSTAT1, IFN-β and CXCL10 levels were analyzed in RAW264.7 cells and CT26 tumor-bearing tissues. In addition, the effect of BY101921 on the type Ⅰ interferon signaling pathway was systematically evaluated. Results: BY101921 demonstrated outstanding selectivity as a PARP7 inhibitor, displaying limited off-target effects on PARP1/2, reducing the risk of systemic toxicity, especially hematologic effects. In mice and dogs, BY101921 revealed favorable PK characteristics following oral administration. In vivo, BY101921 exhibited potent inhibition of tumor growth as a monotherapy, and its combination with anti-PD-1 further enhanced its anti-tumor efficacy, with excellent tolerability in animals. Mechanism of action studies showed that BY101921 generated an anti-tumor immune response by upregulating pSTAT1 levels and promoting the secretion of IFN-β and CXCL10, thereby restoring the type Ⅰ interferon signaling pathway. Conclusions: BY101921, a potent and selective PARP7 inhibitor, demonstrates significant anti-tumor efficacy both as a monotherapy and in combo with anti-PD-1, while maintaining excellent tolerability in animal models. With favorable drug-like properties and a promising safety profile, BY101921 holds potential as an enhanced therapeutic option for cancer patients. At present, clinical studies investigating BY101921 as a single agent and in combo with anti-PD-1 are in the recruitment phase.
A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of fadraciclib, an oral CDK2/9 inhibitor, in patients with advanced solid tumors and lymphoma.
Authors: Miguel Angel Villalona-Calero, Do-Youn Oh, Elena Garralda, Maria Vieito, Julius Huang, Sarina A. Piha-Paul
Journal: Journal of Clinical Oncology (2024)

3125 Background: Fadraciclib (formerly CYC065)is a highly selective inhibitor of CDK2 (IC 50 = 5 nM) and CDK9 (IC 50 =26 nM) causing mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations. In a previous Phase 1 study of intravenous fadraciclib monotherapy, a heavily pretreated endometrial cancer patient with CDNK2A, CDKN2B and PRMT5 loss achieved confirmed CR. This is the first study to evaluate oral fadraciclib monotherapy. Methods: A global Phase 1/2, open-label, dose-escalation study in subjects with advanced solid tumors or lymphoma (NCT04983810). The Phase 1 portion is exploring both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D using a standard 3+3 design. Results: As of January 31, 2024, 45 subjects have received fadraciclib at 8 dose levels (DL1-6a: 50-150 mg, bid given 3-5 days per week for 3-4 out of 4 weeks or DL6b: 125 mg, daily for 4/4 weeks). Heavily pretreated patients with breast, colorectal, gynecological cancers, and T cell lymphoma with ECOG PS 0:1 (9:36) were enrolled. Fadraciclib was well tolerated at dose levels 1 to 5 (up to 100 mg bid). Adverse events reported were nausea (n=31), vomiting (n=23), thrombocytopenia (n=6). Grade 3 DLT of hyperglycemia (1/2 DL6 and 2/6 DL6a) and nausea (1/2 DL6) was observed at doses above 125mg bid M-F, 4/4 weeks. Hyperglycemia was controlled after dose interruption and blood glucose levels returned to normal range after treatment. Preliminary PK analysis suggests dose dependent exposure. At DL5 and above, plasma concentration was above target concentration from CDK2 and CDK9 target engagement studies. Preliminary PD analysis of treated patient samples showed suppression of expression in multiple target genes, including MYC, MCL1, CCNE/cyclin E, CDKN2A, CDKN2B, and PRMT5. Preliminary efficacy data are available for 31 evaluable patients. Two PRs after the first cycle were observed in one patient with CTCL and one with angioimmunoblastic T-Cell Lymphoma (AITL). Twenty patients showed SD. Tumor size reduction was observed in 10 patients. A squamous NSCLC patient harboring a CDK2NB loss of function mutation and prior chemo- and immunotherapy achieved reduction of 22% in the sum of all target lesions after 1 cycle of treatment. Conclusions: Based on data from the CYC065-101 study, fadraciclib appears well tolerated from DL1 to 5. The MTD for the bid dosing schedule is 100mg bid, M-F, 4/4 weeks. The trial is ongoing with evaluation of a daily dosing schedule. Clinical trial information: NCT04983810 .
Phase 1/2 trial of the HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab: Clinical update.
Authors: Marcus Smith Noel, Kurt C. Demel, Bhaskar Srivastava, Scott R. Daigle, Scott Boiko, Amanda Hoerres, Frank G. Basile, Xinyan Zhang, Patricia Fraser, Sue Dasen, Daria Chabas, Esha A. Gangolli, Rama Balaraman, Sunil Sharma, Martin Gutierrez, David Sommerhalder
Journal: Journal of Clinical Oncology (2024)

3083 Background: NDI-101150 is a potent, selective, oral inhibitor of hematopoietic progenitor kinase 1 (HPK1), with a different immunotherapy mechanism to other checkpoint inhibitors. NDI-101150 reactivates anti-tumor activity of T-cells, B-cells and dendritic cells (DCs), even under immunosuppressive conditions. Methods: Safety and preliminary efficacy (primary endpoints) of NDI-101150 alone (50–200 mg once-daily in 28-day cycles) and in combination with pembrolizumab are being assessed in patients (pts) with relapsed or metastatic solid tumors. NDI-101150 monotherapy expansion cohorts in renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and gastric/gastroesophageal (G/GEJ) cancer are also being assessed. Results: Dose escalation/expansion data as of Dec 13, 2023 are presented. Treatment (tx)-related adverse effects (TRAEs) in the safety set (N=39) for NDI-101150 monotherapy are presented in the table. 30 (76.9%) pts reported ≥1 TRAE and 5 (12.8%) pts reported grade ≥3 TRAEs. Most common TRAEs were nausea, vomiting, diarrhea and fatigue. Combination tx TRAEs (N=7) recapitulate the monotherapy profile (data not shown). NDI-101150 induced clinical benefit in 4/24 (16.7%) response-evaluable pts: complete response in 1 pt with clear cell RCC; stable disease (SD) ≥6 months in 3 pts (RCC [21 months], pancreatic cancer and endometrial cancer). Unconfirmed SD was noted in 2 pts with RCC, and in 1 pt each with NSCLC and G/GEJ cancer. Nearly dose-proportional increases in exposure were observed on Day 1 of Cycle 1 (C1) across 50–200 mg, with steady state achieved between Days 15 and 28 of tx. Pharmacokinetic profiles of monotherapy and combination tx cohorts were similar. Sustained inhibition of pSLP76 of &gt;50% relative to pre-tx levels (predicted to achieve efficacy in nonclinical models) was observed at all doses tested by Day 15 of C1. Using a custom 12-plex immunofluorescence assay to monitor changes in the tumor immune microenvironment, an on-tx biopsy assessment from a pt with RCC showed increased infiltration of activated CD8+ T-cells and DCs compared to archival biopsy, aligning with the proposed mechanism of action. Conclusions: The observed clinical benefit and safety profile support continued evaluation of NDI-101150 as a viable next-generation immunotherapeutic. Clinical trial information: NCT05128487 . [Table: see text]