Molecular-targeted Agents Research Articles

Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database.

Clinical utility of comprehensive genomic profiling (CGP) for precision medicine has become evident. Although there are several reports on the genomic landscape of GI stromal tumors (GISTs), large-scale data specific to GIST are limited, especially in Asia. Additionally, the applicability of molecular-targeted agents identified using CGP has not been extensively examined. We investigated the status of genomic alterations in Japanese patients with advanced GISTs using the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database to identify novel treatment strategies and drug development. We retrospectively reviewed the clinical and CGP data of patients with advanced-stage GIST registered in the C-CAT database to assess the genomic landscape and potential actionable alterations. Data from 144 patients were reviewed. Oncogenic alterations were detected frequently in KIT (78%), CDKN2A (37%), CDKN2B (29%), RB1 (11%), STK11 (10%), TP53 (9%), PDGFRA (6%), and SDHB (6%). Loss of CDKN2A/CDKN2B was only observed in KIT/PDGFRA-mutated GISTs, while alterations in SDHA/SDHB were only detected in KIT/PDGFRA wild-type GISTs. Among 119 KIT/PDGFRA-mutated GISTs, 95 (80%) had oncogenic genomic alterations and 29 (24%) had actionable alterations, excluding KIT and PDGFRA. However, among 25 KIT/PDGFRA wild-type GISTs, 22 (88%) had oncogenic alterations and 11 (44%) had actionable alterations. Representative candidate drugs for genome-matched therapies in KIT/PDGFRA-mutated and wild-type GISTs were as follows: pembrolizumab for tumor mutation burden-high in one and two patients, respectively; poly-adenosine diphosphate ribose polymerase inhibitors for alterations related to homologous recombination deficiency in 12 and one patient, respectively; NTRK inhibitor for ETV6-NTRK3 fusion in one with KIT/PDGFRA wild-type GIST; and human epidermal growth factor receptor 2-antibody-drug conjugate in one with KIT/PDGFRA-mutated GIST. This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.

Targeted regulation of autophagy using sorafenib-loaded biomineralization nanoenzyme for enhanced photodynamic therapy of hepatoma

Sorafenib (SF), a multi-targeted tyrosine kinase inhibitor, serves as a primary therapeutic modality for advanced liver cancer. Nonetheless, its clinical efficacy is hindered by various obstacles, such as limited bioavailability and inadequate accumulation. This study introduces a novel biomimetic mineralization enzyme, known as BSA@Pt/Ce6/SF@M (PCFM). The PCFM incorporates platinum (Pt) as a catalytic agent, SF as a molecular-targeted therapeutic agent, and Ce6 as a photosensitizer within liver cancer cell membranes. This strategy enables the combination of various anti-tumor treatments, such as photodynamic therapy (PDT) and autophagy induction, leading to increased bioavailability of SF and achieving a multidimensional synergistic anticancer effect. The PDT effect produced by Ce6 in PCFM greatly enhances SF-induced autophagy, effectively promoting autophagic cell death. Furthermore, Pt dissociates from the biomineralization process, acquiring peroxidase properties through chemokinetic reactions. This facilitates the catalysis of significant oxygen generation, addressing the challenge of hypoxia in the tumor microenvironment and improving the efficacy of PDT. Moreover, the SF further enhances therapeutic efficacy by inducing autophagy in response to energy deprivation, as indicated by the reduced levels of HIF-1α, p62, along with increased levels of ROS and LC3-Ⅱ/Ι. This biomineralization-based nanoenzyme exhibits strong anti-tumor characteristics, offering a novel strategy for overcoming challenges in liver cancer treatment.

A New Self-Expandable Metallic Stent with Low Axial Force and a High Axial Force Zero-Border Shows a Very Low Perforation Rate in Malignant Colorectal Obstruction: A Japanese Multicenter Prospective Study.

Background: Recently, there has been a significant increase in the utilization of self-expandable metallic stents (SEMSs) for treating malignant colorectal obstructions through colorectal stenting. The mechanical properties of SEMSs are usually considered to affect clinical outcomes of patients with malignant colorectal obstructions. Methods: This single-arm, prospective, multicenter study of SEMS with a lower axial force and high axial force zero-border included 200 patients with malignant colorectal obstruction. Technical and clinical success, stent patency, and adverse events associated with SEMS placement were evaluated. Results: One patient was excluded, and 199 patients were evaluated. The treatment intent was bridge-to-surgery in 129 and palliation in 70 patients. Technical and clinical success rates were 99.5% and 97.0%, respectively. The percentage of the ColoRectal Obstruction Scoring System scores of 3 or higher improved significantly from 19.2% before placement to 93.9% after placement. Clinical success was not achieved in five patients due to insufficient stent expansion in four patients and stent occlusion in one patient. Only one patient underwent emergency surgery for perforation of the proximal colon, far from where the stent was placed; the rescue procedure was not performed, despite no improvement in proximal dilatation due to insufficient stent expansion. Among the palliation cohort, 15 patients received chemotherapy, including molecular-targeted agents such as bevacizumab. There were no fatal cases related to stent placement. Conclusions: For management of malignant colorectal obstruction, this newly developed SEMS with low axial force and a high axial force zero-border showed high technical and clinical success rates, and an extremely low perforation rate (0.5%).

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy

BackgroundIntegrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy.MethodsWe screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments.ResultsOur combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib’s off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR.ConclusionIn the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

Targeted HER2-positive cancer therapy using ADAPT6 fused to horseradish peroxidase

Targeted cancer therapy is a promising alternative to the currently established cancer treatments, aiming to selectively kill cancer cells while sparing healthy tissues. Hereby, molecular targeting agents, such as monoclonal antibodies, are used to bind to cancer cell surface markers specifically. Although these agents have shown great clinical success, limitations still remain such as low tumor penetration and off-target effects. To overcome this limitation, novel fusion proteins comprised of the two proteins ADAPT6 and Horseradish Peroxidase (HRP) were engineered. Cancer cell targeting is hereby enabled by the small scaffold protein ADAPT6, engineered to specifically bind to human epidermal growth factor receptor 2 (HER2), a cell surface marker overexpressed in various cancer types, while the enzyme HRP oxidizes the nontoxic prodrug indole-3-acetic acid (IAA) which leads to the formation of free radicals and thereby to cytotoxic effects on cancer cells. The high affinity to HER2, as well as the enzymatic activity of HRP, were still present for the ADAPT6-HRP fusion proteins. Further, in vitro cytotoxicity assay using HER2-positive SKOV-3 cells revealed a clear advantage of the fusion proteins over free HRP by association of the fusion proteins directly to the cancer cells and therefore sustained cell killing. This novel strategy of combining ADAPT6 and HRP represents a promising approach and a viable alternative to antibody conjugation for targeted cancer therapy.

Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs’ half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. Statement of significanceTreatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Real-world performance of the digital drug-assignment system for precision oncology in lung cancer.

e13590 Background: Precision medicine has profoundly transformed lung cancer treatment, an array of molecularly targeted agents (MTAs) are approved and used in clinical practice. Comprehensive molecular testing is key in treatment decisions, nevertheless, interpretation of complex molecular profiles can be challenging and subjective. Previously we demonstrated that digital drug assignment (DDA), an algorithmic computational reasoning model that ranks associated targeted therapies based on the totality of individual tumor genomic data, rather than matching one drug to one biomarker, was predictive of relative benefit of the agents as used in the SHIVA01 trial (1). Here, we collected real-world clinical outcome data from lung cancer patients who received decision support where DDA was integrated to aid a molecular tumor board (MTB) and investigated the effectiveness of administered therapies. Methods: Between 2018 and 2022, 111 lung cancer patients were involved in our precision oncology program. Following molecular diagnostic tests, analysis of the individual molecular profiles and scoring of associated drugs (DDA score) was performed by the DDA system as previously described. The output was assessed by the MTB that provided a strategy to the clinicians who made the final therapy decisions. Treatment courses and outcomes were collected from hospital health records and analyzed. Treatment lines were categorized as the following: high-score MTA (1000≤DDA score), low-score MTA (DDA score<1000), and standard of care (SOC). Results: Overall response rate (ORR) of high-score MTA lines administered following DDA-based decision support (n=13) was 69%, whereas of other treatment lines (low-score MTAs and SOC; n=55) it was 16% (p<0.001); and 26% in low-score MTA lines (n=34; p=0.017). Median progression-free survival (mPFS) of high-score MTA lines administered following DDA-based decision support (n=13) was 63 months (95% CI: 12.0 – 66.0), whereas it was 9 months both for any other treatment lines (low-score MTAs and SOC; n=44; 95% CI: 5.0 – 66.0; p<0.001) and for low-score MTA lines only (n=27; 95% CI: 5.0 – 66.0; p<0.001). Median overall survival (mOS) of patients who received at least one line of high-score MTA after decision support (n=13) was significantly longer than of those who only received non-high score treatments after decision support (patients only treated with low-score MTAs and/or SOC, n=34): not reached vs. 32 months (95% CI 24.0 – not reached), respectively (p=0.012). Conclusions: This study revealed that the DDA system is predictive of relative benefit of the various agents as used in lung cancer care, in line with our previous clinical validation. Validated algorithmic AI-guided drug assignment methods represent a new class of tools that can potentially address challenges in utilizing the results of complex molecular profiles in routine clinical setting. 1. Petak et al., 2021, npj Precis. Onc. 5, 59.

Combining immune checkpoint inhibitors and molecular-targeted agents with hepatic arterial infusion chemotherapy for hepatocellular carcinoma with inferior vena cava and/or right atrium tumor thrombus.

e16177 Background: Patients with hepatocellular carcinoma and inferior vena cava and/or right atrium tumor thrombus (HCC-IVC/RATT) have a poor prognosis and lack evidence for standard first-line systemic treatment due to its low incidence. This study aims to evaluate the effectiveness and safety of three treatments in HCC-IVC/RATT patients: immune checkpoint inhibitors plus molecular-targeted agents (ICI-MTA), hepatic arterial infusion chemotherapy (HAIC), and their combination (ICI-MTA-HAIC). Methods: This multicenter retrospective cohort study included consecutive HCC-IVC/RATT patients who received ICI-MTA, HAIC, or ICI-MTA-HAIC from June 1, 2014, to December 31, 2022. The propensity score matching (PSM) was used to balance baseline characteristics. Survival analysis was conducted using Kaplan-Meier curves and compared using the log-rank test. Results: A total of 243 HCC-IVC/RATT patients were included, with 144 receiving ICI-MTA-HAIC, 29 receiving ICI-MTA, and 70 receiving HAIC. Before PSM, the ICI-MTA-HAIC group had significantly superior median overall survival (OS) of 16.5 months, progression-free survival (PFS) of 8.0 months, and objective response rate (ORR) of 47.9%, in comparison to both the ICI-MTA (OS: 7.7 months, P < 0.001; PFS: 3.5 months, P = 0.001; ORR: 24.1%, P = 0.019) and HAIC groups (OS: 9.1 months, P = 0.003; PFS: 4.9 months, P = 0.007; ORR: 25.7%, P = 0.002) among HCC-IVC/RATT patients based on RECIST v1.1 criteria. The ICI-MTA and HAIC groups didn’t exhibit significant differences in OS, PFS, or ORR ( P = 0.061, 0.043, 0.869, respectively). After PSM, similar results were obtained across the three groups. All adverse reactions were manageable, and no unexpected adverse reactions or treatment-related deaths were observed among the three groups. Conclusions: ICI-MTA-HAIC was a safe and effective therapy that prolonged the survival of HCC-IVC/RATT patients compared to ICI-MTA or HAIC.

Insights from C-CAT repository: A novel approach to identifying appropriate patient populations for anticancer drug development using the clinicogenomic nationwide database in Japan.

11159 Background: The integration of Comprehensive Genomic Profiling (CGP) with real-world data (RWD) provides crucial insights for anticancer drug development to achieve precision oncology, therefore, the current global trend to construct as the national projects, yet its clinical impact remains underexplored. The therapeutic efficacy of each line of anti-cancer drug in various cancer types and the relationship between genetic alterations and the effect of anticancer drugs is needed to guide the direction of future drug development promptly and precisely. Methods: A comprehensive analysis was conducted on data from Japan's Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository between June 2019 and December 2023. Five genomic profiling assays for CGP testing were reimbursed by nation-wide insurance in Japan. Utilizing the clinicogenomic repository of C-CAT, registered data of therapeutic efficacy of anticancer drug including cytotoxic agents, molecular-targeted agents, and immune checkpoint inhibitors were evaluated in association with genetic alterations. Data on anticancer drug of patients (pts) with recurrent or metastatic disease were included in the analysis. Results: The C-CAT registry data encompassed 60,256 pts across 32 tumor organ sites, classified ontology by the OncoTree over 4.5 years. Of these patients, 30,234 were male, and 30,017 were female, with 5 classified as unknown. In terms of age, 31,919 pts were < 65. The most registered origins were colorectal (n=10,110), pancreas (n=8,069), biliary tract (n=5,030), breast (n=3,744), esophagus/stomach (n=3,734), prostate (n=3,701), ovarian/fallopian tube (n=3,521), lung (n=3,427), and soft tissue (n=2,568). TP53mutations (58.3%, n=35,102) were most prevalent, followed by KRAS (25.8%, n=15,521), APC (19.9%, n=11,919), NOTCH3 (14.1%, n=8,502), and PIK3CA (13.0%, n=7,861). The frequency of BRCA1/2mutation was 4.1% (n=2,479). Overall response rate (ORR) for the first-, second-, third-, and fourth-lines treatment were 35.7%, 23.3%, 19.4%, and 19.2%, respectively. Pts treated with cisplatin or carboplatin in the first-line treatment, who had TP53 mutations, showed a better ORR than those without (44.0% vs. 38.9%, p < 0.001). Similarly, pts with BRCA1/2mutation showed a better ORR than those without (53.9% vs. 41.4%, p < 0.001) in the first-line treatment. Conclusions: This study was the first to report the relationship between genetic alterations and the therapeutic effect of anticancer drugs in each line. This approach based on big data analysis potentially accelerates drug development in the appropriate patient population by identifying significant associations between specific genetic mutations and improved outcomes with certain chemotherapy regimens in various cancers.

Clinical landscape of precision oncology for rare cancers among diverse Asian populations: Insights from the MASTER KEY registry.

3024 Background: Despite considerable strides in novel cancer treatments, disparities in access and care persist globally. This is particularly pronounced for rare cancers and among Asian patient cohorts, presenting a dual challenge. Methods: We conducted an analysis on clinical and biomarker data from the MASTER KEY Study, a multi-regional, prospective, observational precision oncology initiative encompassing 3,764 rare cancer patients across Asia. Clinical treatment and biomarker data, inclusive of DNA/RNA sequencing, were scrutinized to compare precision oncology adoption across various countries. Results: Within the Japanese cohort (3,268 patients), predominant rare cancer types included soft tissue sarcomas (22.0%), CNS/brain tumors (12.8%), and head and neck tumors (9.2%). The broader Asian cohort (496 patients) included soft tissue sarcomas (14.6%), liver/biliary tract tumors (14.4%), and head and neck tumors (13.8%), drawing patients from Malaysia, Korea, Taiwan, Philippines, Thailand, and Vietnam. Clinical trial participation for these rare cancers was notably higher in Taiwan (8.2%), followed by Japan (6.5%) and Malaysia (2.0%). The utilization of molecular target agents and/or immune checkpoint inhibitors was highest in Japan (20.3%), trailed by Taiwan (18.9%) and Korea (12.8%). DNA/RNA targeted sequencing data was available for 1,852 patients in Japan (56.7%) and 321 patients (64.7%) across the rest of Asia. 19.5% and 7.0% received on-target therapy in Japan and the rest of Asia, respectively. Notably, in Japan, patients harboring detectable targetable genes like BRAF V600E, BRCA1, and BRCA2 received BRAF/MEK inhibitors and PARP inhibitors at rates of 78.3%, 37.8%, and 25.0%, respectively, with varying response rates of 33.3%, 18.2%, and 20.2% each. Intriguingly, TP53 mutation acted as a negative predictor for response to BRAF/MEK inhibitors. Notably, no patients in the Asian cohort received BRAF/MEK inhibitors or PARP inhibitors despite the detection of these genes. Conclusions: The MASTER KEY Study demonstrates the feasibility of a prospective precision oncology platform, spotlighting rare cancers and enabling on-label targeted therapy as well as off-label targeted therapy for a subset of patients through trials. However, the broader Asian population outside Japan encounters heightened limitations in accessing precision oncology. Urgent expansion of clinical trials throughout Asia is crucial to effectively address the disparity that lies within Asian rare cancer patients.

Abstract PO2-06-06: Effectiveness and prognostic predictors of primary systemic therapy for de-novo Stage IV breast cancer - Supplementary analysis of JCOG1017 PRIM-BC

Abstract Background The optimal choice of drug is important in treating metastatic breast cancer, and the efficacy of the drug should be determined early, especially in cases of progression. On the other hand, untreated de novo Stage IV (dnST-IV) patients are expected to be more sensitive to drugs, but no detailed data are available. In JCOG1017 (Randomized trial of primary tumor resection in dnST-IV), dnST-IV patients were treated with primary systemic therapy for 3 months according to breast cancer subtypes before randomization. We already presented the results of primary endpoint. Primary tumor resection (PTR) could not significantly prolong the overall survival of de-novo stage IV breast cancer patients with sensitivity to primary systemic therapy. We conducted the supplementary analysis of JCOG1017 to clarify the efficacy of primary systemic therapy for dnST-IV and develop optimal treatment strategies for dnST-IV breast cancer. Methods In JCOG1017, systemic therapy was performed for each subtype/metastatic status as follows; 1) hormone therapy: ER+ HER2- and no life-threatening metastases, 2) weekly PTX therapy: life-threatening metastases, or ER-HER2-, 3) trastuzumab + pertuzumab + docetaxel (HPD) therapy OR trastuzumab + paclitaxel (HPTX) therapy: ER-HER2+. 4) hormone therapy: ER+HER2+ and no life-threatening metastases. The non-PD rate (no increase of more than 10% of the sum of the diameters of the target lesions compared before systemic therapy), the responses rate (cCR or cPR), and overall survival (OS) of responder (cCR or cPR)/non-responder (cSD or cPD) and PD/non-PD were examined. Results Among 569 patients who received primary systemic therapy in JCOG 1017, the non-PD rate was 77.2% and the response rate was 29.0% after 3 months of systemic therapy. By subtype, the non-PD rate was 78.2% for ER-HER2-, 75.4% for ER+HER2-, 92.9% for ER-HER2+, and 66.7% for ER+HER2+. The response rate was 36.4% for ER-HER2-, 13.4% for ER+HER2-, 81.0% for ER-HER2+, and 40.3% for ER+HER2+. In multivariable analysis, the non-PD rate was higher in postmenopausal (odds ratio [OR] 1.673, p=0.0240) and PgR-positive (OR 2.391, p= 0.0019) patients besides subtypes. Analysis results by drug were as follows; 1) hormone therapy (non-PD rate: 72.9%) was more effective for PgR-positive (OR 3.258, p< 0.0001), less effective for patients with visceral metastasis (OR 0.605, p=0.0334) and HER2-positive (OR 0.365, p=0.0016), 2) wPTX (non-PD rate: 76.1%) was no significant predictors of efficacy, 3) HPD/HPTX (non-PD rate: 92.7%) was more effective in patients with visceral metastasis (OR 15.818, p=0.0030). PD patients had much worse OS (hazard ratio [HR] 0.501, p< 0.0001) compared to non-PD, whereas responders had a little worse OS (HR 0.788, p=0.0538) compared to non-responders. Similar tendency was observed in any drug. Discussion Predictors of response to primary systemic therapy differed by subtype, with the need for treatment strategies tailored to PgR, HER2 expression, and the status of visceral metastasis. In the ER+HER2+ group, the efficacy of hormonal therapy alone was low, and combination therapy with molecular-targeted agents was considered necessary. The non-PD rate reflected prognosis in determining the efficacy of primary systemic therapy for dnST-IV. Citation Format: Tadahiko Shien, Akihiko Shimomura, Makoto Ishitobi, Kiyo Tanaka, Takahiro Tsukioki, Takashi Yamanaka, Fumitaka Hara, Kenjiro Aogi, Yasuhiro Yanagita, Michiko Tsuneizumi, Naohito Yamamoto, Hiroshi Matsumoto, Akihiko Suto, Ken-ichi Watanabe, Michiko Harao, Chizuko Kanbayashi, Mitsuya Ito, Keisei Anan, Shigeto Maeda, Keita Sasaki, Gakuto Ogawa, Haruhiko Fukuda, Hiroji Iwata. Effectiveness and prognostic predictors of primary systemic therapy for de-novo Stage IV breast cancer - Supplementary analysis of JCOG1017 PRIM-BC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-06.

Usefulness of atezolizumab plus bevacizumab as second-line therapy for patients with unresectable hepatocellular carcinoma.

To clarify the efficacy of atezolizumab (ATZ) plus bevacizumab (BEV) as the second-line therapy for patients with unresectable hepatocellular carcinoma (HCC). The subjects were 82 patients with HCC receiving ATZ/BEV, including 33 patients with previous therapies with molecular-targeted agents (MTA). Therapeutic efficacy was evaluated using contrast-enhanced CT according to the mRECIST. The Child-Pugh scores were 5, 6,7 and 8 in 40, 35, 5 and 2 patients, respectively, and the extents of HCC progression were BCLC stage A, B and C in 3, 31 and 48 patients, respectively. Early therapeutic efficacy was evaluated in 67 patients, and percentages of patients achieving CR/PR/SD/PD until 12 weeks were 3.0%/29.9%/49.3%/17.9%, respectively, indicating ORR of 32.8% and DCR of 82.1%, The ORR was higher in MTA-naïve patients (40.5%) than in those after discontinuation of lenvatinib due to PD (7.7%, P = 0.0410), while the DCR was equivalent between both patients (83.3% vs 80.0%, P = 0.1184), and the multivariate analysis revealed previous MTA therapies with lenvatinib alone as a factor to deteriorate the ORR (HR of 4.846 (P = 0.0619)). The OS rates at 24 and 48 weeks were 86% and 72%, respectively, and the rates did not differ between MTA-naïve and MTA-experienced patients. Multivariate analyses revealed that achievement of CR, PR or SD and peripheral neutrophil/lymphocyte ratio were associated with a favorable outcome (HR of 0.124, P<0.0001 and 0.351, P = 0.0303). ATZ/BEV merits consideration even for MTA-experienced patients, since the OS was equivalent to those in MTA-naïve patients despite of an unfavorable early therapeutic efficacy.

Prognostic and Immunotherapeutic Predictive Value of CAD Gene in Hepatocellular Carcinoma: Integrated Bioinformatics and Experimental Analysis.

Hepatocellular carcinoma (HCC) is a common type of cancer that ranks first in cancer-associated death worldwide. Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are the key components of the pyrimidine pathway, which promotes cancer development. However, the function of CAD in HCC needs to be clarified. In this study, the clinical and transcriptome data of 424 TCGA-derived HCC cases were analyzed. The results demonstrated that high CAD expression was associated with poor prognosis in HCC patients. The effect of CAD on HCC was then investigated comprehensively using GO annotation analysis, KEGG enrichment analysis, Gene Set Enrichment Analysis (GSEA), and CIBERSORT algorithm. The results showed that CAD expression was correlated with immune checkpoint inhibitors and immune cell infiltration. In addition, low CAD levels in HCC patients predicted increased sensitivity to anti-CTLA4 and PD1, while HCC patients with high CAD expression exhibited high sensitivity to chemotherapeutic and molecular-targeted agents, including gemcitabine, paclitaxel, and sorafenib. Finally, the results from clinical sample suggested that CAD expression increased remarkably in HCC compared with non-cancerous tissues. Loss of function experiments demonstrated that CAD knockdown could significantly inhibit HCC cell growth and migration both in vitro and in vivo. Collectively, the results indicated that CAD is a potential oncogene during HCC metastasis and progression. Therefore, CAD is recommended as a candidate marker and target for HCC prediction and treatment.

Multicenter validation study of a treatment selection MAP for pancreatic neuroendocrine tumors.

Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP. Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP. There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P=0.032) as the only significant independent favorable predictive factor. The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP.

The Real-Life Impact of Primary Tumor Resection of Synchronous Metastatic Colorectal Cancer-From a Clinical Oncologic Point of View.

The complex medical care of synchronous metastatic colorectal (smCRC) patients requires prudent multidisciplinary planning and treatments due to various challenges caused by the primary tumor and its metastases. The role of primary tumor resection (PTR) is currently uncertain; strong arguments exist for and against it. We aimed to define its effect and find its best place in our therapeutic methodology. We performed retrospective data analysis to investigate the clinical course of 449 smCRC patients, considering treatment modalities and the location of the primary tumor and comparing the clinical results of the patients with or without PTR between 1 January 2013 and 31 December 2018 at the Institute of Oncotherapy of the University of Pécs. A total of 63.5% of the 449 smCRC patients had PTR. Comparing their data to those whose primary tumor remained intact (IPT), we observed significant differences in median progression-free survival with first-line chemotherapy (mPFS1) (301 vs. 259 days; p < 0.0001; 1 y PFS 39.2% vs. 26.6%; OR 0.56 (95% CI 0.36-0.87)) and median overall survival (mOS) (760 vs. 495 days; p < 0.0001; 2 y OS 52.4 vs. 26.9%; OR 0.33 (95% CI 0.33-0.53)), respectively. However, in the PTR group, the average ECOG performance status was significantly better (0.98 vs. 1.1; p = 0.0456), and the use of molecularly targeted agents (MTA) (45.3 vs. 28.7%; p = 0.0005) and rate of metastasis ablation (MA) (21.8 vs. 1.2%; p < 0.0001) were also higher, which might explain the difference partially. Excluding the patients receiving MTA and MA from the comparison, the effect of PTR remained evident, as the mOS differences in the reduced PTR subgroup compared to the reduced IPT subgroup were still strongly significant (675 vs. 459 days; p = 0.0009; 2 y OS 45.9 vs. 24.1%; OR 0.37 (95% CI 0.18-0.79). Further subgroup analysis revealed that the site of the primary tumor also had a major impact on the outcome considering only the IPT patients; shorter mOS was observed in the extrapelvic IPT subgroup in contrast with the intrapelvic IPT group (422 vs. 584 days; p = 0.0026; 2 y OS 18.2 vs. 35.9%; OR 0.39 (95% CI 0.18-0.89)). Finally, as a remarkable finding, it should be emphasized that there were no differences in OS between the smCRC PTR subgroup and metachronous mCRC patients (mOS 760 vs. 710 days, p = 0.7504, 2 y OS OR 0.85 (95% CI 0.58-1.26)). The role of PTR in smCRC is still not professionally justified. Our survey found that most patients had benefited from PTR. Nevertheless, further prospective trials are needed to clarify the optimal treatment sequence of smCRC patients and understand this cancer disease's inherent biology.

Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation

Transcriptional programs governed by YAP play key roles in conferring resistance to various molecular-targeted anticancer agents. Strategies aimed at inhibiting YAP activity have garnered substantial interest as a means to overcome drug resistance. However, despite extensive research into the canonical Hippo–YAP pathway, few clinical agents are currently available to counteract YAP-associated drug resistance. Here, we present a novel mechanism of YAP stability regulation by MAP3K3 that is independent of Hippo kinases. Furthermore, we identified MAP3K3 as a target for overcoming anticancer drug resistance. Depletion of MAP3K3 led to a substantial reduction in the YAP protein level in melanoma and breast cancer cells. Mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at serine 405. This MAP3K3-mediated phosphorylation event hindered the binding of the E3 ubiquitin ligase FBXW7 to YAP, thereby preventing its p62-mediated lysosomal degradation. Robust YAP activation was observed in CDK4/6 inhibitor-resistant luminal breast cancer cells. Knockdown or pharmacological inhibition of MAP3K3 effectively suppressed YAP activity and restored CDK4/6 inhibitor sensitivity. Similarly, elevated MAP3K3 expression supported the prosurvival activity of YAP in BRAF inhibitor-resistant melanoma cells. Inhibition of MAP3K3 decreased YAP-dependent cell proliferation and successfully restored BRAF inhibitor sensitivity. In conclusion, our study reveals a previously unrecognized mechanism for the regulation of YAP stability, suggesting MAP3K3 inhibition as a promising strategy for overcoming resistance to CDK4/6 and BRAF inhibitors in cancer treatment.

Abstract 1654: Anti-tumor activity of orally-available cyclic peptide LUNA18 through direct RAS inhibition in RAS-altered tumors

Abstract RAS is the one of the most frequently altered genes in human cancer and contributes to the growth of tumors. Recently, KRAS G12C inhibitors were approved as the first molecular targeting agents for RAS, but there are still huge unmet medical needs in RAS-mutated cancers because drugs targeting non-KRAS G12C tumors have not yet been approved and efficacy by even approved KRAS G12C inhibitors is not satisfactory. LUNA18 is the cyclic peptide that binds to RAS mutants and wildtype, including KRAS, NRAS and HRAS, thereby inhibiting protein-protein interaction (PPI) between the inactive form of RAS and GEFs (guanine nucleotide exchange factors). LUNA18 decreased the active form of KRAS and phosphorylated ERK and AKT, and cell proliferation in RAS-mutated cancer cells with nM order of cellular IC50s irrespective of tumor types and amino acid substitutions except for Q61 mutants. On the other hand, LUNA18 did not inhibit proliferation of cells with active mutations downstream of RAS (BRAF and MEK), suggesting LUNA18 selectively inhibited growth of RAS-dependent cells. Consistent with in vitro cellular activity, oral administration of LUNA18 showed durable RAS signal inhibition up to 24-48 hours and tumor regression in RAS-mutated xenograft models. In addition to KRAS-mutated cells, LUNA18 also showed in vitro and in vivo robust efficacy in KRAS-amplified cells. These data indicated LUNA18 is the versatile compound that selectively suppressed cellular signaling from RAS G12/G13 mutants as well as RAS wildtype amplification through inhibition of PPI between the inactive form of RAS and GEFs, and it can be applicable to a wide range of RAS-altered tumors. Rebound of the MAPK pathway is reported to be the one of the cause for attenuating efficacy of KRAS G12C inhibitors. We also observed the rebound of ERK activation 24-72 hours after the treatment with a KRAS G12C inhibitor in cells with the KRAS G12C mutation though suppression of KRAS activity was maintained. On the other hand, LUNA18 persistently suppressed ERK activity as well as KRAS activity up to 72 hours. The combination of the KRAS G12C inhibitor with siRNA for RAS wildtype showed durable inhibition of ERK activity, suggesting that RAS wildtype plays a key role for the rebound of ERK activity and inhibitory activity to RAS wildtype by LUNA18 contribute to the persistent inhibition of RAS signaling by LUNA18. We orally administered LUNA18 and a KRAS G12C inhibitor to a xenograft model, which showed temporal response and then acquired resistance to a KRAS G12C inhibitor, and found that LUNA18 significantly suppressed emergence of resistance to a KRAS G12C inhibitor. These results supported that the combination of the KRAS G12C inhibitor with LUNA18 could be a promising option to patients with KRAS G12C mutation by suppressing resistance to a KRAS G12C inhibitor through the suppression of rebound of the MAPK pathway. Citation Format: Hitoshi Sase, Saki Michisaka, Yukako Tachibana, Masami Hasegawa, Toshihiko Fujii, Kana Takei, Tomoko Kanei, Naoaki Murao, Shino Kuramoto, Norihito Shibahara, Atsushi Ohta, Mikimasa Tanada, Takuya Shiraishi, Hitoshi Iikura, Takehisa Kitazawa, Hiroshi Tanaka. Anti-tumor activity of orally-available cyclic peptide LUNA18 through direct RAS inhibition in RAS-altered tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1654.

Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer.

Enhanced knowledge of the interaction of cancer cells with their environment elucidated the critical role of tumor microenvironment in tumor progression and chemoresistance. Cancer-associated fibroblasts act as the protagonists of the tumor microenvironment, fostering the metastasis, stemness, and chemoresistance of cancer cells and attenuating the anti-cancer immune responses. Gastric cancer is one of the most aggressive cancers in the clinic, refractory to anti-cancer therapies. Growing evidence indicates that cancer-associated fibroblasts are the most prominent risk factors for a poor tumor immune microenvironment and dismal prognosis in gastric cancer. Therefore, targeting cancer-associated fibroblasts may be central to surpassing resistance to conventional chemotherapeutics, molecular-targeted agents, and immunotherapies, improving survival in gastric cancer. However, the heterogeneity in cancer-associated fibroblasts may complicate the development of cancer-associated fibroblast targeting approaches. Although single-cell sequencing studies started dissecting the heterogeneity of cancer-associated fibroblasts, the research community should still answer these questions: "What makes a cancer-associated fibroblast protumorigenic?"; "How do the intracellular signaling and the secretome of different cancer-associated fibroblast subpopulations differ from each other?"; and "Which cancer-associated fibroblast subtypes predominate specific cancer types?". Unveiling these questions can pave the way for discovering efficient cancer-associated fibroblast targeting strategies. Here, we review current knowledge and perspectives on these questions, focusing on how CAFs induce aggressiveness and therapy resistance in gastric cancer. We also review potential therapeutic approaches to prevent the development and activation of cancer-associated fibroblasts via inhibition of CAF inducers and CAF markers in cancer.

Consensus statement on the management of late-onset rheumatoid arthritis.

Late-onset rheumatoid arthritis (LORA), which has been increasing in recent years, lacks evidence for initial treatment. Japanese rheumatology experts recognized this gap and addressed it by developing consensus statements on the first clinical application of LORA. These statements were created following an introductory discussion about treatment fundamentals, which included a review of existing literature and cohort data. The steering committee created a draft, which was refined using a modified Delphi method that involved panel members reaching a consensus. The panel made decisions based on input from geriatric experts, clinical epidemiologists, guideline developers, patient groups, and the LORA Research Subcommittee of the Japan College of Rheumatology. The consensus identified four established facts, three basic approaches, and six expert opinions for managing LORA. Methotrexate was recommended as the primary treatment, with molecular-targeted agents being considered if treatment goals cannot be achieved. An emphasis was placed on assessing the lives of older patients due to challenges in risk management and methotrexate accessibility caused by comorbidities or cognitive decline. The experts substantiated and refined 13 statements for the initial treatment of LORA. To validate these claims, the next is to conduct a registry study focusing on new LORA cases.

Financial toxicity and patient experience associated with financial burden of molecular-targeted and immune therapies for cancer: an observational study under public health insurance

BackgroundFinancial burden of cancer treatment can negatively affect patients and their families. This study aimed to evaluate the financial toxicity of patients treated with molecular-targeted and immune therapies and explore the relationship between financial toxicity and patient experiences associated with the financial burden of cancer treatment.MethodsThis anonymous, self-administered questionnaire survey conducted across nine hospitals in Japan included patients aged 20–60 years who were receiving molecular-targeted agents or immune checkpoint inhibitors for any type of cancer for ≥ 2 months. Financial toxicity was evaluated using the COmprehensive Score for Financial Toxicity (COST). Patient experience was examined using 11 items based on previous studies. Independent factors related to financial toxicity were explored using multiple regression analyses.ResultsThe mean COST score was 17.0 ± 8.4, and 68 (49.3%) participants reported COST scores at or below the cutoff point. The factors contributing to financial toxicity were “hesitation regarding continuing treatment based on finances” (sβ = − 0.410, p < 0.001), “cutting through my deposits and savings” (sβ = − 0.253, p = 0.003), and “reducing spending on basics like food or clothing” (sβ = − 0.205, p = 0.046) along with comorbidities (sβ = − 0.156, p = 0.032).ConclusionPatients receiving molecular-targeted and immune therapies are at risk of experiencing profound financial toxicity and a reduced quality of life. The independently related factors that we identified have the potential to serve as indicators of profound financial toxicity and the need for specialized intervention.