Diverse Tumor Types Research Articles

Population Pharmacokinetic and Pharmacodynamic Analysis of Navtemadlin in Patients with Relapsed and Refractory (R/R) Myelofibrosis (MF) and Other Myeloid or Solid Tumor Malignancies

Background:Murine double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, is overexpressed in malignancies such as MF and Merkel cell carcinoma (MCC). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumors. Navtemadlin has been tested in 21- or 28-day treatment cycles, with 5 or 7 consecutive days of dosing per cycle. Navtemadlin elicits plasma concentration-dependent increases in serum macrophage inhibitory cytokine-1 (MIC-1). An increase in MIC-1 relative to baseline MIC-1 serum concentration is a key pharmacodynamic (PD) marker of response to navtemadlin treatment (Zhang et al. Xenobiotica 2022). A population pharmacokinetic (PK) model was developed, based on patients with R/R MF (N=113, NCT03662126); MCC (N=35, NCT03787602); solid tumors and multiple myeloma (ST/MM N=105, Gluck et al. Invest New Drugs 2019); R/R acute myeloid leukemia (AML, N=35, Erba et al. Blood Adv 2019); and healthy volunteers (HV, N=30, Wong et al. Clin Pharmacol Drug Dev 2022).The objectives wereto characterize navtemadlin PK and covariate effects and compare steady-state (SS) PK and PD across cancer types. Methods:A two-compartment PK model with first-order absorption and elimination was estimated using NONMEM ® (first-order conditional estimation with interaction). Four transit compartments captured absorption. Inter-subject variability was modeled as lognormal. A stepwise covariate search used forward addition (p<0.05) followed by backward elimination (p<0.01). Log-transformed SS MIC-1 ratio to baseline (fold ratio) was tested in a fixed-effects linear regression model with respect to SS exposures, with baseline MIC-1 as the covariate. The final population PK and MIC-1 models were evaluated by inspection of parameter tables, by overlaying model predictions with observed data, and by standard residual diagnostics. Results:The PK estimation used 5,282 concentrations from 318 subjects, including 1,415 concentrations in 113 patients with R/R MF. Tumor type affected absorption rate (median, 0.635/hr in MCC; slower vs other types), apparent clearance (median, 8.90 L/hr in MCC; lower vs other types), and apparent central volume (median, 64.4 L in MCC; similar to AML, but lower vs other types) (Table 1). Accordingly, simulated SS area under the curve (AUCss) differed across populations in the order MCC>AML>MF>ST/MM = HV (Figure 1). Covariate analysis indicated median AUC increased with the inflammation marker C-reactive protein, by 21% at 90 th percentile CRP, and with age, by 5% at 90 th percentile age of 75 y, compared to the median, 66 y. Men had 24% lower relative bioavailability than women. Taking navtemadlin with food slowed absorption by 10% but had no impact on AUCss. Other tested covariates, including body weight, creatinine clearance, aspartate transaminase, alanine transaminase, bilirubin, albumin, alpha 1-acid glycoprotein, race, UGT1A1 genotype, recent ruxolitinib treatment in MF, and CYP3A4 inducer/inhibitor concomitant medications, were not significant. Median MIC-1 fold ratio increased with navtemadlin AUCss. Higher baseline MIC-1 resulted in lower SS MIC-1 fold ratio. Median baseline MIC-1 differed by tumor type. In R/R MF, baseline MIC-1 was 2,297 ng/L and SS fold ratio of MIC-1 was 7.79 (N=91). In MCC, baseline MIC-1 was 1,718 ng/L and SS fold ratio of MIC-1 was 16.7 (N=29). In R/R MF, higher baseline spleen volume was also associated with lower SS MIC-1 fold ratio. Exposure-MIC-1 relationships in R/R MF and MCC were generally similar to other tumor types and HV populations (Allard et al. Hemasphere 2019; Zhang et al. Xenobiotica 2022). Conclusions:Tumor type influenced navtemadlin exposure with simulated exposure in R/R MF patients at the selected Phase 3 dose of 240 mg comparable to exposures in MCC patients at 180 mg, the selected Phase 2 dose for that indication. Cancer-associated inflammation and/or treatment history, as well as age and female sex, may increase navtemadlin exposure. The PD marker MIC-1 responds to navtemadlin in a concentration-dependent fashion. The overall SS fold change of MIC-1 PD responses was lower in disease states or subjects with higher baseline MIC-1. These studies demonstrate potent, dose-dependent PK/PD responses following p53 activation with the novel MDM2 inhibitor, navtemadlin, across diverse tumor types.

Establishment of a novel indicator of pyroptosis regulated gene transcription level and its application in pan-cancer

Pyroptosis is a type of programmed cell death and plays a dual role in distinct cancers. It is elusive to evaluate the activation level of pyroptosis and to appraise the involvement of pyroptosis in the occurrence and development of diverse tumors. Accordingly, we herein established an indicator to evaluate pyroptosis related gene transcription levels based on the expression level of genes involved in pyroptosis and tried to elaborated on the association between pyroptosis and tumors across diverse tumor types. We found that pyroptosis related gene transcription levels could predict the prognosis of patients, which could act as either a favorable or a dreadful factor in diverse cancers. According to signaling pathway analyses we observed that pyroptosis played a significant role in immune regulation and tumorigenesis and had strong links with other forms of cell death. We also performed analysis on the crosstalk between pyroptosis and immune status and further investigated the predictive potential of pyroptosis level for the efficacy of immunotherapy. Lastly, we manifested that pyroptosis status could serve as a biomarker to the efficacy of chemotherapy across various cancers. In summary, this study established a quantitative indicator to evaluate pyroptosis related gene transcription levels, systematically explored the role of pyroptosis in pan-cancer. These results could provide potential research directions targeting pyroptosis, and highlighted that pyroptosis may be used to develop a novel strategy for the treatment of cancer.

Successes and challenges in modeling heterogeneous BRAFV600E mutated central nervous system neoplasms.

Central nervous system (CNS) neoplasms are difficult to treat due to their sensitive location. Over the past two decades, the availability of patient tumor materials facilitated large scale genomic and epigenomic profiling studies, which have resulted in detailed insights into the molecular underpinnings of CNS tumorigenesis. Based on results from these studies, CNS tumors have high molecular and cellular intra-tumoral and inter-tumoral heterogeneity. CNS cancer models have yet to reflect the broad diversity of CNS tumors and patients and the lack of such faithful cancer models represents a major bottleneck to urgently needed innovations in CNS cancer treatment. Pediatric cancer model development is lagging behind adult tumor model development, which is why we focus this review on CNS tumors mutated for BRAFV600E which are more prevalent in the pediatric patient population. BRAFV600E-mutated CNS tumors exhibit high inter-tumoral heterogeneity, encompassing clinically and histopathological diverse tumor types. Moreover, BRAFV600E is the second most common alteration in pediatric low-grade CNS tumors, and low-grade tumors are notoriously difficult to recapitulate in vitro and in vivo. Although the mutation predominates in low-grade CNS tumors, when combined with other mutations, most commonly CDKN2A deletion, BRAFV600E-mutated CNS tumors are prone to develop high-grade features, and therefore BRAFV600E-mutated CNS are a paradigm for tumor progression. Here, we describe existing in vitro and in vivo models of BRAFV600E-mutated CNS tumors, including patient-derived cell lines, patient-derived xenografts, syngeneic models, and genetically engineered mouse models, along with their advantages and shortcomings. We discuss which research gaps each model might be best suited to answer, and identify those areas in model development that need to be strengthened further. We highlight areas of potential research focus that will lead to the heightened predictive capacity of preclinical studies, allow for appropriate validation, and ultimately improve the success of "bench to bedside" translational research.

Cell-Free miRNAs as Non-Invasive Biomarkers in Brain Tumors.

Diagnosing brain tumors, especially malignant variants, such as glioblastoma, medulloblastoma, or brain metastasis, presents a considerable obstacle, while current treatment methods often yield unsatisfactory results. The monitoring of individuals with brain neoplasms becomes burdensome due to the intricate tumor nature and associated risks of tissue biopsies, compounded by the restricted accuracy and sensitivity of presently available non-invasive diagnostic techniques. The uncertainties surrounding diagnosis and the tumor's reaction to treatment can lead to delays in critical determinations that profoundly influence the prognosis of the disease. Consequently, there exists a pressing necessity to formulate and validate dependable, minimally invasive biomarkers that can effectively diagnose and predict brain tumors. Cell-free microRNAs (miRNAs), which remain stable and detectable in human bodily fluids, such as blood and cerebrospinal fluid (CSF), have emerged as potential indicators for a range of ailments, brain tumors included. Numerous investigations have showcased the viability of profiling cell-free miRNA expression in both CSF and blood samples obtained from patients with brain tumors. Distinct miRNAs demonstrate varying expression patterns within CSF and blood. While cell-free microRNAs in the blood exhibit potential in diagnosing, prognosticating, and monitoring treatment across diverse tumor types, they fall short in effectively diagnosing brain tumors. Conversely, the cell-free miRNA profile within CSF demonstrates high potential in delivering precise and specific evaluations of brain tumors.

Metabolic programs of T cell tissue residency empower tumour immunity.

Tissue resident memoryCD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memoryCD8+ T cell populations. We found that memory CD8+T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memoryT cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memoryCD8+ T cell formation in the context of acute infections and enhance antitumour immunity.

Abstract PR012: SETD2 safeguards the genome against isochromosome formation

Abstract Chromosome mis-segregation during cell division occurs in diverse tumor types, promoting aneuploidy and intratumoral genetic heterogeneity. While the mechanisms that govern chromosome segregation are well-established, how changes in the activities of tumor suppressors or oncogenes drive mitotic errors remain poorly understood. Loss of the tumor suppressor SETD2, the methyltransferase responsible for tri-methylation of histone 3 lysine 36 (H3K36me3), correlates with clear cell renal cell carcinoma (ccRCC) tumors exhibiting extensive intratumoral heterogeneity. Yet, how loss of H3K36me3 or SETD2 promotes heterogeneity is unknown. Here, we show that loss of SETD2 promotes chromosome mis-segregation during mitosis and interphase DNA bridges driven by the formation of dicentric chromosomes. Cytogenetic analyses revealed that these dicentrics loss were largely comprised of mirror-imaged isodicentric chromosomes that contain two active centromeres. In addition to isodicentrics, cells lacking SETD2 or H36K36me3 generated iso- and acentric chromosomes, however loss of SETD2 protein additionally caused chromosome instability. These data directly link loss of a tumor suppressor to these mutable chromatin structures that initiate intratumor heterogeneity by promoting gross chromosomal rearrangements. Citation Format: Frank M. Mason, Anteneh T. Tebeje, Emily S. Kounlavong, Rashmi Dahiya, Logan Vlach, Tiffany Guess, Ruhee Dere, Ryoma Ohi, Peter Ly, Cheryl L. Walker, W. Kimryn Rathmell. SETD2 safeguards the genome against isochromosome formation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR012.

An Updated Overview on the Synthesis and Anticancer Evaluation of Quinazoline Derivatives

AbstractCancer, a leading global cause of death, necessitates the exploration of safer and more effective anticancer drugs due to the adverse side effects associated with current cytotoxic treatments. Quinazoline and its derivatives have emerged as a promising class of drugs with demonstrated efficacy against diverse tumor types. In light of these advancements, this comprehensive review aims to outline recent developments in the utilization of quinazoline derivatives as anticancer agents. Additionally, the article offers valuable insights into the potential for novel quinazoline derivatives to serve as future anticancer drugs. By delving into the structure‐activity relationship study, this review equips researchers with a thorough understanding necessary for designing a substantial number of impactful quinazoline compounds, which hold great potential in the treatment of various life‐threatening disorders.

WD Repeat and HMG Box DNA Binding Protein 1: An Oncoprotein at the Hub of Tumorigenesis and a Novel Therapeutic Target.

WD repeat and HMG-box DNA binding protein 1 (WDHD1) is a highly conserved gene from yeast to humans. It actively participates in DNA replication, playing a crucial role in DNA damage repair and the cell cycle, contributing to centromere formation and sister chromosome segregation. Notably, several studies have implicated WDHD1 in the development and progression of diverse tumor types, including esophageal carcinoma, pulmonary carcinoma, and breast carcinoma. Additionally, the inhibitor of WDHD1 has been found to enhance radiation sensitivity, improve drug resistance, and significantly decrease tumor cell proliferation. This comprehensive review aims to provide an overview of the molecular structure, biological functions, and regulatory mechanisms of WDHD1 in tumors, thereby establishing a foundation for future investigations and potential clinical applications of WDHD1.

FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy

Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood vessels, and their presence is generally associated with poor patient prognosis. Here we show that the transcription factor, Foxc2, promotes VM in diverse solid tumor types by driving ectopic expression of endothelial genes in tumor cells, a process that is stimulated by hypoxia. VM-proficient tumors are resistant to anti-angiogenic therapy, and suppression of Foxc2 augments response. This work establishes co-option of an embryonic endothelial transcription factor by tumor cells as a key mechanism driving VM proclivity and motivates the search for VM-inhibitory agents that could form the basis of combination therapies with anti-angiogenics.

Generation of whole tumor cell vaccine for on-demand manipulation of immune responses against cancer under near-infrared laser irradiation

The therapeutic efficacy of whole tumor cell vaccines (TCVs) is modest, which has delayed their translation into personalized immunotherapies in the clinic. Here, we develop a TCV platform based on photothermal nanoparticle-loaded tumor cells, which can be rationally applied to diverse tumor types to achieve on-demand boost of anti-tumor immune responses for inhibiting tumor growth. During the fabrication process, mild photothermal heating by near-infrared (NIR) laser irradiation induces the nanoparticle-bearing tumor cells to express heat shock proteins as endogenous adjuvants. After a single vaccination at the back of tumor-bearing mice, non-invasive NIR laser irradiation further induces mild hyperthermia at vaccination site, which promotes the recruitment, activation, and antigen presentation by dendritic cells. Using an indicator we term fluctuation of tumor growth rate, we determine appropriate irradiation regimens (including optimized irradiation intervals and times). This TCV platform enables on-demand NIR manipulation of immune responses, and we demonstrate potent therapeutic efficacy against six murine models that mimick a range of clinical scenarios, including a model based on humanized mice and patient-derived tumor xenografts.

CBF-Beta Mitigates PI3K-Alpha-Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer.

Loss of either NEDD9 or BCL-XL confers hypersensitivity to PI3K-alpha inhibition whereas loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.

Gender Differences and miRNAs Expression in Cancer: Implications on Prognosis and Susceptibility.

MicroRNAs are small, noncoding molecules of about twenty-two nucleotides with crucial roles in both healthy and pathological cells. Their expression depends not only on genetic factors, but also on epigenetic mechanisms like genomic imprinting and inactivation of X chromosome in females that influence in a sex-dependent manner onset, progression, and response to therapy of different diseases like cancer. There is evidence of a correlation between miRNAs, sex, and cancer both in solid tumors and in hematological malignancies; as an example, in lymphomas, with a prevalence rate higher in men than women, miR-142 is "silenced" because of its hypermethylation by DNA methyltransferase-1 and it is blocked in its normal activity of regulating the migration of the cell. This condition corresponds in clinical practice with a more aggressive tumor. In addition, cancer treatment can have advantages from the evaluation of miRNAs expression; in fact, therapy with estrogens in hepatocellular carcinoma determines an upregulation of the oncosuppressors miR-26a, miR-92, and miR-122 and, consequently, apoptosis. The aim of this review is to present an exhaustive collection of scientific data about the possible role of sex differences on the expression of miRNAs and the mechanisms through which miRNAs influence cancerogenesis, autophagy, and apoptosis of cells from diverse types of tumors.

Targeted immune activation in pediatric solid tumors: opportunities to complement local control approaches.

Surgery or radiation therapy is nearly universally applied for pediatric solid tumors. In many cases, in diverse tumor types, distant metastatic disease is present and evades surgery or radiation. The systemic host response to these local control modalities may lead to a suppression of antitumor immunity, with potential negative impact on the clinical outcomes for patients in this scenario. Emerging evidence suggests that the perioperative immune responses to surgery or radiation can be modulated therapeutically to preserve anti-tumor immunity, with the added benefit of preventing these local control approaches from serving as pro-tumorigenic stimuli. To realize the potential benefit of therapeutic modulation of the systemic response to surgery or radiation on distant disease that evades these modalities, a detailed knowledge of the tumor-specific immunology as well as the immune responses to surgery and radiation is imperative. In this Review we highlight the current understanding of the tumor immune microenvironment for the most common peripheral pediatric solid tumors, the immune responses to surgery and radiation, and current evidence that supports the potential use of immune activating agents in the perioperative window. Finally, we define existing knowledge gaps that limit the current translational potential of modulating perioperative immunity to achieve effective anti-tumor outcomes.

Prognostic and immunological significance of key gluconeogenesis regulators, PCK1 and PCK2, in human cancers especially kidney renal clear cell carcinoma: Insights from pan-cancer analysis, PCKs signature construction, and in vitro experiments

BackgroundMetabolic reprogramming is a significant feature of tumor cells, and targeting metabolic pathways has become a viable strategy for cancer therapy. Gluconeogenesis is essential to glucose metabolism, with phosphoenolpyruvate carboxykinase 1 (PCK1) and phosphoenolpyruvate carboxykinase 2 (PCK2) as key enzymes. The roles of PCK1 and PCK2 in various cancers remain unclear. MethodsWe conducted a comprehensive overview of PCK1 and PCK2 in human cancers, assessing their expression and association with prognosis, tumor immunity, and drug sensitivity. Prognostic relevance, synergistic effects, and potential binding activity were also investigated. ResultsPCK1 and PCK2 expression were downregulated in most cancer types, displaying heterogeneity between and within tumors. Their effects on prognosis were bidirectional with synergistic interactions. PCK1 and PCK2 expression correlated with immune subtypes, tumor mutational burden, microsatellite instability, immune checkpoints, and immune cell infiltration. Expression variation was observed in diverse or specific tumor types. The association with drug sensitivity indicated the potential for targeting PCK1 and PCK2 to improve drug resistance. A PCKs signature was constructed respectively, confirming their pro-oncogenic role in adrenocortical carcinoma and oncogenic role in kidney renal clear cell carcinoma (KIRC). Experimental validation identified their significant impact on KIRC, with some binding molecules identified through drug prediction and molecular docking. ConclusionsOur study revealed the key roles of PCK1 and PCK2 in tumorigenesis, metastasis, tumor immunity, and metabolic activity, suggesting their potential as therapeutic targets, particularly for KIRC.

Hsa_circ_0001741 Suppresses Ovarian Cancer Cell Proliferations Through Adsorption of miR-188-5p and Promotion of FOXN2 Expression.

Ovarian cancer (OC) is among several general malignant gynecological cancers associated with high mortality rates on a global scale. Earlier investigations have revealed a critical role of circular RNAs (circRNAs) in OC development, which is a new class of endogenous non-coding RNA (ncRNA) that reported to mediate progression of diverse tumor types. At present, the precise involvement of circRNAs and associated regulatory mechanisms in OC remain unknown. In this study, hsa_circ_0001741 expression patterns in OC cells and tissues were tested. The underlying regulatory pathways and targets were further explored with the aid of bioinformatics, luciferase reporter, 5-ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) analyses. Further investigation of the hsa_circ_0001741 effects on tumor growth in vivo revealed abnormal circRNA expression in OC. hsa_circ_0001741 expression reduced in OC cells and tissues, indicative of activity in OC progression. hsa_circ_0001741 upregulation resulted in OC proliferation inhibitions. The luciferase reporter outputs verified miR-188-5p and FOXN2 as hsa_circ_0001741 downstream targets. FOXN2 silencing or miR-188-5p upregulations reversed inhibitory effects regarding hsa_circ_0001741 on OC cell proliferation. Therefore our data suggested that hsa_circ_0001741 upregulation inhibited proliferation of OC through modulatory effects on miR-188-5p/FOXN2 signaling.

Hsa_circ_0014784-induced YAP1 promoted the progression of pancreatic cancer by sponging miR-214-3p

ABSTRACT Background Pancreatic cancer (PC) is one of the most common gastrointestinal tumors globally. Former investigations discovered that circular RNAs (circRNAs) play an important role in PC development. circRNAs belong to a new class of endogenous noncoding RNAs, which have been found to mediate the progression of diverse types of tumors. Nevertheless, the roles of circRNAs and the underlying regulatory mechanisms in PC remain unknown. Methods In this study, our team employed next-generation sequencing (NGS) to examine the abnormal circRNA expression in PC tissues. The circRNA expression in PC cell lines and tissues was detected. Then, regulatory mechanism and targets were examined with bioinformatics analysis, luciferase reporting analysis, Transwell migration, 5-ethynyl−2′-deoxyuridine, and CCK−8 analysis. An in vivo experiment was employed to elucidate hsa_circ_0014784 roles in PC tumor growth and metastasis. Results The results showcased abnormal circRNA expression in PC tissues. Our lab also found that hsa_circ_0014784 expression incremented in PC tissues and cell lines, implying that hsa_circ_0014784 functioned in PC progression. hsa_circ_0014784 downregulation inhibited PC proliferation and invasion in vivo and in vitro. The bioinformatics and luciferase report data validated that both miR−214-3p and YAP1 were hsa_circ_0014784 binding partners. The overexpression of YAP1 reversed the migration, proliferation, and epithelial – mesenchymal transition (EMT) of PC cells and the angiogenic differentiation of HUVECs after miR−214-3p overexpression. Conclusion Taken together, our study found that hsa_circ_0014784 downregulation decremented invasion, proliferation, EMT, and angiogenesis of PC by regulating miR−214-3p/YAP1 signaling.

Generalizable FGFR prediction across tumor types using self supervised learning.

e15057 Background: Deep Learning models have demonstrated the ability to detect tumors, classify disease state, or infer genetic biomarkers from digital whole slide images (WSI) of Hematoxylin and Eosin (H&E)-stained tissue. Such models can be deployed to improve clinical practice or efficiently recruit for clinical trials. However, the data to train these models is often very limited and image capture protocols vary between labs. We propose to use Self Supervised Learning (SSL) on large unlabeled histopathology data sets to improve generalizability and predictive performance of deep learning models on unseen data. Methods: We pre-trained a Convolutional Neural Network (CNN) using SSL on 25,120 unlabeled, digital WSIs from various sources (multiple scanners, hospital systems, labs, diseases, tissue sites). We then fine-tuned the pre-trained CNN to infer the presence or absence of select FGFR alterations in Muscle Invasive Bladder Cancer (MIBC) from the digital WSI. We applied this model (FGFRSSL) to WSIs of biopsies from other data sources and tumor types and compared with a model (FGFRTRAD) that was trained exclusively on MIBC samples without self-supervised learning. Results: The FGFRSSL model achieved an Area Under ROC Curve (AUC = 0.80) on MIBC WSIs and maintained performance on images from an independent lab (AUC=0.82). We further show that the model generalizes to Non-Muscle Invasive Bladder Cancer (NMIBC) samples with (AUC = 0.76) and Pan-Tumor WSIs (AUC: 0.83). The FGFRTRAD model trained without SSL-based pre-training achieved an Area Under ROC Curve (AUC: 0.76) on MIBC WSIs was less generalizable, showing lower performance for independent data (AUC = 0.72), NMIBC samples (AUC = 0.72), and Pan-Tumor samples (AUC = 0.64). Conclusions: We leveraged SSL pretraining to improve the reliability and generalizability of AI-based models across multiple data sources. We also demonstrate our model’s ability to infer FGFR status across multiple solid tumor types after training on only MIBC samples, suggesting the cell morphology conferred by FGFR alteration in cancer may be shared across diverse tumor types. These models represent a means for efficiently screening patients for actionable clinical biomarkers in a robust manner to guide clinical decisions and inform drug development efforts. [Table: see text]

A phase 1, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of PF-07799933 (ARRY-440) as a single agent and in combination therapy in participants 16 years and older with advanced solid tumors with BRAF alterations.

TPS3164 Background: Approved BRAF inhibitors (BRAFi) are inactive against RAF dimers. Accordingly, the acquisition of BRAF dimers ( e.g., through drug-acquired splice variants or BRAF amplification) may lead to therapy resistance. Non-V600 (class II and III) BRAF alterations that occur de novo in diverse tumor types also signal as dimers and therefore have no approved targeted therapeutic options. Additional liabilities of approved BRAFi include toxicity from paradoxical activation of wild-type (WT) RAF and limited brain penetration, a common primary and metastatic site for BRAF-altered cancers. In contrast to approved agents, investigational BRAFi inhibit WT and mutant RAF proteins (A, B, and C-RAF, monomers, dimers), and therefore may be limited by on-target toxicity from “pan-RAF” inhibition. PF-07799933 is an oral selective ATP-competitive small-molecule RAF kinase inhibitor that suppresses BRAF signaling in BRAF V600-mutant and non-V600- BRAF mutant tumors. It displays significantly less paradoxical activation than approved BRAFi and is not “pan RAF” as it spares non-BRAF-containing RAF dimers. We describe here the Phase 1 study of PF-07799933 as monotherapy or in combination with binimetinib or cetuximab in participants with BRAF-altered advanced solid tumors. Methods: The purpose of this first-in-human study is to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and potential clinical benefits of PF-07799933 administered as a single agent and in combination in participants with BRAF Class I, II and III mutated solid tumors with or without brain involvement. Part 1 (monotherapy dose escalation) and Part 2 (combination dose escalation) will enroll participants with BRAF V600 mutation who have progressed on a approved BRAFi or with de novo Class II or III alterations who have progressed on standard of care therapy. The primary objective of Part 1 is to determine monotherapy MTD/RDE of PF-07799933. Participants in Part 1 will be allowed to add on rational combination with either binimetinib or cetuximab at the time of disease progression. Once PK measurements indicate the potential for significant BRAF inhibition in the brain, participants with untreated and symptomatic brain metastases will be allowed to enroll. The primary objective of Part 2 is combination MTDc/RDEc of PF-07799933 with binimetinib or cetuximab. The primary objective of Part 3 is efficacy in defined cohorts (total ~120 participants): Cohort 1-2: BRAF V600 mutant melanoma; Cohort 3: BRAF Class II altered melanoma; Cohorts 4-5: BRAF V600 and Class II altered CRC; Cohort 6: other BRAF V600, Class II/III altered solid tumor not qualifying for Cohorts 1-5. Clinical trial information: NCT05355701 .

Comprehensive 0utcomes for After Cancer Health: COACH.

TPS12141 Background: The landscape for cancer survivors continues to evolve as individuals live longer following primary therapy. For some, treatment is complete; for others, active surveillance or maintenance therapy may be indicated. Individual survivorship needs are diverse, influenced by tumor and treatment type, as well as social determinants of health. Digital interventions may support survivors in achieving personalized health goals throughout survivorship. The Comprehensive Outcomes for After Cancer Health (COACH) Study (NCT05349227) explores the feasibility of a digital health coaching (DHC) program for individuals enrolled with diverse tumor types and geographic regions. Methods: COACH is a multi-center, randomized, wait-list control trial enrolling 550 individuals ≥18 years old who are within 1-year of completion of primary cancer therapy at enrollment. Up to 100 participants, will be recruited at each of 6 study sites, of which 3 are currently enrolling. Consented individuals are randomized to 6 months of DHC or 6 months of data collection only, then cross-over for follow-up to 12-months. Both groups wear an activity tracker; complete patient reported outcome measures; and provide fecal specimens. The DHC program includes weekly Health Advisor calls and supplemental delivery of evidenced-based content via text, email or mobile platform. Topics fall in health domains of physical, mental/emotional, financial, social, and sexual, and emphasize nutrition, physical activity, sleep, and screening for recurrent or de novo cancer. Feasibility for this study is defined as a retention rate greater than or equal to 70%, and acceptability will be defined as less than or equal to 20% scoring “not at all helpful.” Trends over time will be assessed using linear mixed models using time as a fixed effect, as well as any covariates and interactions of interest. Descriptive statistics will be used to evaluate exploratory endpoints. A cross-cohort end-point related to physical function as measured by the PROMIS Physical Function 10a, will also be evaluated. To date, 72 individuals have enrolled, with Nebraska as the lead site, including 71 women, with a mean age of 61.78 (Range 33-74), from the U.S. Midwest (n = 57) and Northeast (n = 15). 4 identify as African American/Black, 68 as White. 50 have a breast, 13 ovarian, 8 endometrial, 1 gastric diagnosis. Nine have completed the first 6 months of the study. The study is novel in the breadth of data collected and potential to understand variability in patient experiences and provide insights into the feasibility, acceptability, and efficacy of a DHC intervention supporting individuals after primary cancer treatment. Clinical trial information: NCT05349227 .

First results from the RETgistry: A global consortium for the study of resistance to RET inhibition in RET-altered solid tumors.

9065 Background: Rearranged during transfection ( RET) gene alterations are the oncogenic driver in diverse tumor types, including RET fusions identified in 1-2% of non-small cell lung cancers (NSCLC). While RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are effective, acquired drug resistance remains a challenge. Here, we report the initial results from the RETgistry, an international consortium aimed at elucidating mechanisms of resistance to RET TKIs across RET-altered solid tumors. Methods: This was a retrospective analysis performed across 16 institutions. Patients (pts) were eligible if they had advanced solid tumor harboring an oncogenic RET alteration, received ≥1 RET TKI with disease progression, and underwent resistant tumor or liquid biopsy for next-generation sequencing (NGS). Results: A total of 103 time-distinct biopsies (62 tissue, 30 plasma, 11 paired tissue/plasma) were included in analysis, obtained from 88 pts with progression on a RET-selective TKI [selpercatinib (n = 70), pralsetinib (n = 14), selpercatinib and pralsetinib sequentially (n = 4)]. Pts had the following tumor types: 72 NSCLC (69% KIF5B-RET, 21% CCDC6-RET, 10% other RET fusion), 13 medullary thyroid cancer (TC) (54% RET M918T, 46% other RET mutation), and 2 papillary and 1 anaplastic TC (all, RET fusion). Median age was 58 (range, 21-86); 48% were male with 89% never/light smokers. Median duration of RET TKI preceding biopsies [first-line, n = 32 (31%); second-line, n = 42 (41%); third-/greater-line, n = 29 (28%)] was 16.5 months (mos) (95% CI, 14.0-19.6); median PFS was 14.1 mos (95% CI, 9.3-17.0). Resistant biopsies were obtained at median 15.0 mos from TKI initiation (range, 1.8-58.8). Acquired RET mutations were detected in 14 (14%), most common being G810 substitutions in 12 (12%). Potential off-target resistance gene alterations identified in 43 cases (42%) included MET amplification (14%), BRAF V600E or fusion (2%), KRAS gain or mutation (5%), ERBB2 amplification (2%), EGFR amplification (3%), ROS1 fusion (1%), and activating PIK3CA mutation or PTEN loss (4%). No resistant lung cancer biopsy demonstrated small cell transformation. The duration of TKI therapy (HR 0.64, p = 0.11) or PFS (HR 0.75, p = 0.33) did not differ according to the presence of on-target vs off-target resistance. NGS analyses of pre-RET-selective TKI tumors (n = 92) revealed frequent co-occurring alterations in TP53 (29%) and CDKN2A/B (12%). Conclusions: On-target resistance to RET inhibition due to acquired RET mutations was less common than off-target resistance, identified in 14%. The majority of RET TKI resistance is mediated by off-target mechanisms such as bypass receptor tyrosine kinase activation. Further studies are warranted to enable the development of therapeutic strategies to address resistance in pts with RET-altered tumors. The RETgistry accrual and data analyses continue.