Dual-targeted Therapy Research Articles

Computer-aided Drug Discovery of Epigenetic Modulators in Dual-target Therapy of Multifactorial Diseases.

Numerous studies suggest that common genetic and epigenetic factors such as p53, histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), the (Ataxia Telangiectasia mutated) ATM gene, cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase 3 (GSK3) and altered expression of microRNA (miRNA) play a crucial role in cancer and neurodegeneration. As there is growing evidence that epigenetic aberrations in cancer and neurological diseases lead to complex pathophysiological changes, the simultaneous targeting of epigenetic and other related pathways by dual-target inhibitors may contribute to the discovery of more effective and personalized therapeutic options. Computer-Aided Drug Design (CADD) provides comprehensive bioinformatic, chemoinformatic, and chemometric approaches for the design of novel chemotypes of epigenetic dual-target inhibitors, enabling efficient discovery of new drug candidates for innovative treatments of these multifactorial diseases. The detailed anticancer mechanisms by which the epigenetic dual-target inhibitors alter metastatic and tumorigenic properties, influence the tumor microenvironment, or regulate the immune response are also presented and discussed in the review. To improve our understanding of the pathogenesis of cancer and neurodegeneration, this review discusses novel therapeutic agents targeting different molecular mechanisms involved in these multifactorial diseases.

Exploring Dual-Targeted Therapy in the Management of Moderate to Severe Inflammatory Bowel Disease: A Retrospective Study

Abstract Background Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), often results in significant morbidity among patients with moderate to severe forms. While biologics and small molecules are effective in inducing remission, many patients experience refractory disease or extra-intestinal manifestations. This study assesses the safety and efficacy of dual-targeted therapy in IBD patients treated at the Inflammatory Bowel Disease Center. Methods This retrospective cohort study examined 79 patients with UC or CD who received dual-targeted therapy at the University from October 2018 to August 2023. Data collected included demographics, disease characteristics, previous treatments, and clinical outcomes. Primary outcomes were endoscopic, radiographic, and patient-reported clinical improvements, with secondary outcomes focusing on safety profiles. Results Among the 79 patients (42 UC, 37 CD), 97 dual-targeted therapy cases were analyzed, primarily involving a biologic combined with a JAK inhibitor (90.7%). The median therapy duration was 39.1 weeks. Endoscopic improvement occurred in 69% of matched samples, with significant differences between pre- and post-dual-targeted therapy Mayo scores for UC (p = 0.002) and SES-CD scores for CD (p = 0.018). The median pre- and post-dual-targeted therapy Mayo scores across matched samples were 3 (range 1-3) and 1 (range 0-3) respectively, and for SES-CD scores were 12 (range 0-36) and 4 (range 0-20) respectively. Clinical improvement was reported by 73.2% of patients, with notable reductions in ESR (median 19 [range 2-124] mm/hr to 9 [range 0-116] mm/hr, p = 0.006), CRP (median 8.0 [range 0.2-78.5] mg/L to 3.0 [range 0.2-68.2] mg/L, p <0.001) , and albumin levels (4.0 [range 2.2-4.9] mg/dL to 4.2 [range 3.4-5.2], p < 0.001). Non-obesity was associated with both more endoscopic improvement (p = 0.002) and clinical improvement (p = 0.007). Adverse events occurred in 37 cases, predominantly upper respiratory tract infections and dermatologic issues, with no thromboembolic events reported. Discussion Dual-targeted therapy demonstrated efficacy in improving clinical and endoscopic outcomes in patients with severe, refractory IBD, and exhibited an acceptable safety profile. Despite the promising results, further research is needed to confirm these findings and determine optimal therapy combinations.

Efficacy of pyrotinib and capecitabine in recurrent breast cancer with a HER2-negative genetic switch following systemic therapy: A case report and literature review

Despite the demonstrated safety and efficacy of pyrotinib and capecitabine in treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, their efficacy in recurrent breast cancer in which the HER2 status has changed to negative remains unexplored. Here, we report a case of a 38-year-old female diagnosed with invasive ductal adenocarcinoma of the left breast, staged as mcT2N0M0. Fluorescence in situ hybridization (FISH) confirmed that the tumor was hormone receptor (HR) positive with low HER2 expression (2+) and a HER2/CEP17 ratio of 3.56. Following neoadjuvant targeted therapy and chemotherapy, she underwent a modified radical mastectomy. Post-surgical histopathological examination revealed a non-pathological complete response, classified as ypT1cypN1M0. The tumor remained HR positive with low HER2 expression (2+), but the FISH result was negative (HER2/CEP17 ratio of 1.65). For 1 year, she was administered dual-targeted therapy with goserelin and exemestane. Sequential therapy with neratinib was initiated; however, it was discontinued due to grade IV diarrhea. Despite ongoing endocrine therapy, she experienced tumor recurrence on the left chest wall. A biopsy of the recurrent lesion revealed it to be HR positive with low HER2 expression (2+) and a negative FISH result (HER2/CEP17 ratio of 1.33). The recurrent lesion responded to combination therapy consisting of pyrotinib and capecitabine, with tolerable adverse events. This case highlights the potential advantages of combining pyrotinib and capecitabine when the HER2 status changes to negative following systemic therapy.

S1192 Exploring Dual-Targeted Therapy in the Management of Moderate to Severe Inflammatory Bowel Disease: A Retrospective Study

S1192 Exploring Dual-Targeted Therapy in the Management of Moderate to Severe Inflammatory Bowel Disease: A Retrospective Study

Comparison of ustekinumab, infliximab and combination therapy in moderately to severely active ulcerative colitis - a study protocol of a randomized, multicenter, head-to-head COMBO-UC trial.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex etiology that affects the large intestine. Characterized by chronic, bloody diarrhea, UC can lead to severe complications, including an increased risk of colorectal cancer. Despite advancements in conservative treatment, including biologics like anti-TNF agents and ustekinumab (UST), many patients do not achieve full remission. Dual targeted therapy (DTT) combining infliximab (IFX) and UST is a promising approach to improve treatment outcomes. This prospective, randomized, multicenter, head-to-head controlled trial will evaluate the efficacy and safety of UST, IFX, and combination therapy (UST + IFX) in 172 patients with moderate to severe active UC across eight gastroenterology centers in Poland. The study includes a 14-16 week remission induction period followed by a 52-week maintenance phase. Patients will be randomly assigned to one of three treatment arms: IFX monotherapy, UST monotherapy, or IFX + UST combination therapy. Primary endpoint is clinical and endoscopic remission post-induction. Secondary endpoints include clinical response, biochemical remission, histological remission, and quality of life assessments using the Inflammatory Bowel Diseases Questionnaire and 36-Item Short Form Survey. Safety will be monitored through adverse event and serious adverse event reporting. This trial aims to determine whether combining IFX and UST can achieve higher remission rates and better long-term outcomes compared to monotherapy. The results could provide crucial insights into the optimal use of biologic agents in UC treatment, potentially establishing DTT as a standard therapy. The study's design, including extensive follow-up and robust endpoint measures, will contribute to understanding the therapeutic potential and safety profile of this combination therapy.

Combined targeting of Hedgehog/GLI1 and Wnt/β-catenin pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/β-catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co-expression of key proteins from the Hh/GLI1 and Wnt/β-catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/β-catenin pathway with the CBP/β-catenin transcription inhibitor ICG-001, dual-target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S-phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG-001 downregulated GLI1 and β-catenin while upregulating GSK-3β expression. The interaction between Hh/GLI1 and Wnt/β-catenin pathways was mediated by GANT61-dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of β-catenin and decreased the inhibition of GSK-3β in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/β-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

NGS and FISH for MET amplification detection in EGFR TKI resistant non-small cell lung cancer (NSCLC) patients: A prospective, multicenter study in China

ObjectivesComprehensive data using Next-Generation Sequence (NGS) and fluorescence in situ hybridization (FISH) for detecting MET amplification is limited in Chinese patients, we evaluating NGS performance both in tissue and plasma samples using FISH as reference. We also sought to find optimal thresholds value for NGS in detecting MET amplification via bioinformatics methods. MethodPatients progressed after 1st-, 2nd-, or 3rd-generation (G) EGFR-TKIs were enrolled. Tissue biopsy samples were performed for MET amplification detection via both NGS and FISH. Paired plasma samples were collected for MET amplification detection by NGS. The sensitivity, specificity and agreement were analyzed between NGS and FISH. Results116 eligible patients were analyzed. 44 patients were male. 82 patients were after 3rd generation EGFR-TKI. MET amplification was detected in 43 (37.1 %) patients by FISH, including 19 (16.4 %) polysomy and 24 (20.7 %) focal amplification. The positive rate of MET amplification in post 3rd generation EGFR-TKI and post 1st/2ndgeneration EGFR-TKI resistant patients was 42.7 % (35/82), and 23.5 % (8/34).The sensitivity, specificity and agreement of detecting MET amplification by NGS in tissue were 39.5 % (17/43), 98.6 % (72/73) and 76.7 % (89/116), respectively, 66.7 % (16/24), 98.6 % (72/73) and 90.7 % (88/97) for focal MET amplification in tissue and 29.2 % (7/24), 94.5 % (69/73), 78.4 % (76/97) for focal amplification in plasma. Results were shown in the table below. ConclusionNGS is an alternative method for MET focal amplification detection in tissue. While the sensitivity of NGS testing in plasma needs further improvement to maximize identification of patients with potential benefit from dual-targeted therapy.

A bioinspired doxorubicin-carried albumin Nanocage against aggressive Cancer via systemic targeting of tumor and lymph node metastasis

Cancer metastasis and recurrence are obstacles to successful treatment of aggressive cancer. To address this challenge, chemotherapy is indispensable as an essential part of comprehensive cancer treatment, particularly for subsequent therapy after surgical resection. However, small-molecule drugs for chemotherapy always cause inadequate efficacy and severe side effects against cancer metastasis and recurrence caused by lymph node metastases. Here, we developed doxorubicin-carried albumin nanocages (Dox-AlbCages) with appropriate particle sizes and pH/enzyme-responsive drug release for tumor and lymph node dual-targeted therapy by exploiting the inborn transport properties of serum albumin. Inspired by the protein-templated biomineralization and remote loading of doxorubicin into liposomes, we demonstrated the controlled synthesis of Dox-AlbCages via the aggregation or crystallization of doxorubicin and ammonium sulfate within albumin nanocages using a biomineralization strategy. Dox-AlbCages allowed efficient encapsulation of Dox in the core protected by the albumin corona shell, exhibiting favorable properties for enhanced tumor and lymph node accumulation and preferable cellular uptake for tumor-specific chemotherapy. Intriguingly, Dox-AlbCages effectively inhibited tumor growth and metastasis in orthotopic 4T1 breast tumors and prevented postsurgical tumor recurrence and lung metastasis. At the same time, Dox-AlbCages had fewer side effects than free Dox. This nanoplatform provides a facile strategy for designing tumor- and lymph node-targeted nanomedicines for suppressing cancer metastasis and recurrence.

Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia.

MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. Invivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.

A prospective, open-label, single-arm phase II clinical study of inetetamab in combination with pyrotinib and albumin-bound paclitaxel for the neoadjuvant treatment of patients with HER2+ early and locally advanced breast cancer.

e12635 Background: Chemotherapy combined with dual anti-HER2 target therapy has become the standard neoadjuvant therapy regimen for HER2+ breast cancer. Patients achieving pCR have a relatively better prognosis. Inetetamab (Septin) is an innovative HER2 monoclonal antibody drug developed in China. It has been proven to delay the progression of HER2+ metastatic breast cancer patients and bring survival benefits. The purpose of this study was to explore the efficacy and safety of Inetetamab, Pyrotinib and Albumin-bound Paclitaxel in the neoadjuvant treatment of HER2+ breast cancer. Methods: This phase II trial included patients with HER2+ early or locally advanced breast cancer whose tumor size was>20mm or confirmed axillary lymph node metastasis. Patients receive Inetetamab initial dose of 8 mg/kg over 90 minutes IV infusion, followed 6 mg/kg over 30 to 90 minutes IV infusion q3w, Pyrotinib 400 mg orally every day and Albumin-bound Paclitaxel 125mg/m2, IV, D1/8/15, q3w. Patients receive above treatment every 3 weeks for a total of 4 cycles, followed by surgery. After surgery, EC (90mg/m2 of Epirubicin Hydrochloride, 600mg/m2 of Cyclophosphamide, q21 days, 4 cycles) was administered, followed by maintenance treatment with trastuzumab combined with pertuzumab for 1 year. And provide radiotherapy and endocrine therapy to the patient according to the specific situation. The primary endpoint was pathological complete response (pCR). Results: Until February 4, 2024, 18 patients were enrolled, of which 15 had completed surgical treatment. The median age of enrolled patients was 49 years (35-60 years). 66.7% (10 cases) of patients achieved RCB grade 0 (pCR), 26.7% (4 cases) achieved RCB grade I, 6.7% (1 case) achieved RCB grade II. Of the 15 patients, 73.3% (11 cases) were HR+/HER2+, with 72.7% (8 cases) achieved pCR. Among the 4 HR-/HER2+ patients, 50% (2 case) achieved pCR. HR+/HER2+ patients were more likely to achieve pCR than HR-/HER2+ patients. No severe (grade 3/4) toxicity was observed in any patients. Conclusions: Our current data show that the pCR rate in HER2+ breast cancer patients reaches 66.7%, and even 72.7% in HR+ patients. In the previous Neosphere and PEONY studies of the H+P dual target regimen, the pCR of HR+/HER2+patients increased by only 6% and 8.3%, while in the NeoALTTO and PHEDRA studies of the H+L or H+Py regimen, the pCR increased by 18.9% and 17.7%, indicating that the combination of large and small molecules with dual target neoadjuvant therapy for HR+/HER2+ breast cancer was significantly better than that of the monoclonal antibody dual target therapy. Therefore, Inetetamab, Pyrotinib and albumin-bound paclitaxel is a potential effective new adjuvant treatment for HER2+ breast cancer, especially for HR+ patients. Clinical trial information: NCT054444998 .

Efficacy and safety of recombinant humanized anti-HER2 antibody-MMAE conjugate (RC48) in neoadjuvant for HER2-positive breast cancer: A single-arm phase II study.

e12636 Background: Breast cancer patients who achieve pCR after neoadjuvant therapy have a relatively good prognosis. Whether antibody‐drug conjugates (ADCs) can replace traditional chemotherapy combined with dual-target therapy in neoadjuvant therapy still needs to be explored. RC48 is a novel recombinant human anti-HER2 monoclonal antibody conjugated with a microtubule inhibitor (MMAE) via a cleavable linker, which can effectively kill HER2-positive tumors as well as tumors with low or heterogeneous HER2 expression through the bystander effect. The purpose of this study was to evaluate the efficacy and safety of RC48 in neoadjuvant treatment of HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer (size>20mm) or confirmed axillary lymph node metastasis were eligible and received RC48 at a dose of 2.5mg/kg alone every 2 weeks for 6 cycles followed by surgery. EC was administered postoperatively every 21 days for 4 cycles. Trastuzumab combined with pertuzumab was administered for 1 year in the adjuvant setting. The primary endpoints were ORR and pCR rates. Results: 23 patients had been enrolled, and all of them had completed surgical treatment. The median age was 45(38-70) years. The current results showed that 13.0% (3/23) achieved pCR, 78.3% (18/23) achieved PR, and 8.7% (2/23) experienced PD. The ORR was 91.3%. 42% (5/12) of patients with initially positive axillary lymph nodes turned negative after surgery. 11.8% (2/17) HR-/HER2+ patients achieved pCR. According to the proportion of target lesion reduction, patients were divided into mild response (0-50%) and moderate-to-severe response (51%-100%). In the HR-/HER2+ subtype group, 23.5% (4/17) had a mild response, and 76.5% (13/17) had a moderate-to-severe response. 6 patients with HR+ have been enrolled, and 16.7% (1/6) of them achieved pCR. All of HR+ subtypes had a moderate-to-severe response. No relevant serious (grade 3/4) toxicity has been reported. Conclusions: The present data showed an acceptable pCR rate with RC48 in HER2-positive breast cancer. Although the pCR rate was lower than the traditional chemotherapy combined with targeted therapy, the effect of rapid reduction of tumor volume was better (the moderate-severe remission rate was 82.6%). For HR+/HER2+ breast cancer, the ORR in this study reached 100%, indicating that the novel ADC had a significant inhibitory effect on the crosstalk between ER and HER2. And it was expected that the Destiny Breast 11 study would show similar results. This scheme had a good negative conversion rate for patients with positive axillary lymph nodes. Finally, RC48 provided a neoadjuvant treatment option with low toxicity and high patient compliance for HER2-positive breast cancer. Clinical trial information: NCT05134519 .

Guideline concordance of recurrence risk assessment for early breast cancer in a county-level setting in China.

e23263 Background: Guideline-centric risk-based decision-making is crucial for the treatment of HR+HER2- and HER2+ early breast cancer (eBC). However, the consistency of recurrence risk assessment (RA) between real-life clinical practice and guidelines in China has not been thoroughly investigated. As part of the interim analysis of CHASE001 (NCT05544123), we explored the guideline concordance of RA for HR+HER2- and HER2+ eBC in a county-level setting in China. Methods: Cohorts of HR+HER2- and HER2+ eBC patients (pts) from a county-level observational study (CHASE001) were included in this analysis. Clinical recurrence risk were collected for each patient. Descriptive statistics reported the proportion of pts classified into each risk level under real-life assessment by healthcare professionals (HCPs) (H-low/intermediate/high) and guideline-consistent assessment (G-low/intermediate/high). To investigate the factors associated with lower consistency, univariate (UVA) and multivariate logistic regression analysis (MVA) were performed. Results: 1254 HR+HER2- and 841 HER2+ eBC pts from 26 county-level hospitals were included in this analysis. A comparison between recurrence risk under HCPs assessment (HA) and guideline-consistent assessment (GA) revealed divergence. In HR+HER2- cohort, the proportions of pts classified as low, intermediate (int), and high clinical risk for recurrence under HA/GA were 27.2%/2.0%, 48.0%/57.4%, 24.8%/40.6%, respectively. Notably, 36.8% of pts classified as G-int were categorized as H-low, while 47.5% G-high pts were classified as H-int/low. On UVA and MVA, pT1 stage, histological grade 1 and Ki67 < 20% were associated with G-int/H-low; whereas lymphovascular invasion and pN1 were associated with G-high/H-lower. Among 562 G-int/high premenopausal pts, 280 (49.8%) achieved ovarian function suppression (OFS) and the OFS rates were 46.1% in G-int and 55.3% in G-high pts. In HER2+ cohort, the proportions of pts classified as low, int and high risk under HA/GA were 17.2%/0%, 48.2%/51.2% and 34.6%/48.8%. In pts with pN0, 17.2% were classified as H-low and 12% as H-high. In pts with positive lymph nodes (LN+), 11% were classified as H-low and 31% as H-int. Dual anti-HER2 target therapy was administered in 72% of pts with LN+. In both cohorts, HCPs who were medical oncologists had higher consistency with guideline for high-risk evaluation compared to surgical oncologists, whereas surgical oncologists showed higher consistency for int-risk evaluation compared to medical oncologists. Conclusions: This analysis highlights differences in clinical practice between county-level HCPs and guideline recommendations, revealing a significant underestimation of breast cancer recurrence risk. Further efforts should be made to enhance guideline adherence and promote guideline-centric clinical risk-based decision-making at county-level hospitals. Clinical trial information: NCT05544123 .

Abstract PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [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 PO2-04-07.

Abstract PO2-04-02: Trends in Disparities and Transitions of target therapy in Patients With ERBB2 Positive Early Breast Cancer in China and the US, 2011 to 2021

Abstract Background. Diagnosis and treatment of breast cancer have been profoundly improved in China recently. However, trends in disparities and transitions of target treatment in early stage with ERBB2 positive between China and United States are not well known. Methods. This cross-sectional study used Chinese Society of clinical oncology breast cancer (CSCO BC) database from hospitals in 13 provinces of China and Flatiron database from more than 280 US community oncology clinics. Patients with ERBB2 positive and diagnosed as stage I to III breast cancer from 2011 to 2021 were collected. The distribution of target therapy was examined overall and by years. Results. A total of 10245 early-stage breast cancer with ERBB2 positive diagnosed from 2011 to 2021 were screened from the CSCO BC database(n=8446) and the Flatiron Database(n=1799). The median age at diagnosis for Chinese and US was 47 years old and 63 years old. For neoadjuvant therapy, the annual rate of trastuzumab-therapy increased from 0.4% in 2011 to 33% in 2021 in CSCO BC database, while rate of trastuzumab and pertuzumab therapy increased from 0.6% in 2016 to 42% in 2021. The proportion of trastuzumab therapy in Flatiron database decreased from 50% in 2011 to 23% in 2021, while the proportion of dual target therapy increased from 11% in 2013 to 67% in 2021. In adjuvant setting, the trastuzumab therapy increased from 6.8% in 2011 to 37% in 2021 in CSCO BC database, with highest proportion of 65% in 2018. Only 0.1% of patients received dual target therapy in 2018, the proportion increased to 32% in 2021. In Flatiron database, the trastuzumab therapy decreased from 60% in 2011 to 50% in 2021, while rate of trastuzumab and pertuzumab therapy increased from 5% in 2015 to 10% in 2021. Further follow-up is needed for survival data from two databases. Conclusions. Although significant differences were found between the China and US in target therapy, the disparities have been gradually narrowed. Use of trastuzumab in China has overtaken that in US since 2017 attributed to the effort of China's health reform in medical insurance and the promotion of guidelines. Citation Format: Jianbin Li, Jifang Zhou, Haibo Wang, Zhenzhen liu, Zhimin Fan, Yinhua Liu, Cuizhi Geng, Zefei Jiang. Trends in Disparities and Transitions of target therapy in Patients With ERBB2 Positive Early Breast Cancer in China and the US, 2011 to 2021 [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 PO2-04-02.

Abstract PS09-09: Multiomics profiling and molecular classification refine precision treatment strategies for HER2-positive breast cancer

Abstract Background: Anti-HER2 targeted therapy has achieved a series of breakthroughs. However, the current treatment strategy regarding HER2-positive breast cancer remains indiscriminate and lacks specificity, which limits the further improvement of overall treatment response and may lead to overtreatment and extra cost for some patients. Our study aims to reveal the molecular heterogeneity of HER2-positive breast cancer to guide a more precise treatment. Patients and methods: We selected HER2-positive breast cancer patients treated at Fudan University Shanghai Cancer Center between 2013 and 2014 and conducted genomic, transcriptomic, proteomic and metabolomic profiling. We then applied a non-negative matrix factorization algorithm on transcriptomic data to obtain an unsupervised classification. And we further studied the correlation between subtypes and corresponding treatment strategies in multiple cohorts of adjuvant and neoadjuvant therapy. For clinical accessibility, we developed convolutional neural network models through deep learning algorithm based on digital pathology to identify different subtypes. Additionally, we explored novel treatment strategies using the patient-derived organoids (PDOs) models. Results: We established a novel multiomics cohort of 180 HER2- breast cancer patients and classified them into four clinically significant molecular subtypes: (1) A classical HER2-enriched (HER2-CLA, N=51) subtype characterized by strong ERBB2 signaling and remarkable sensitivity to anti-HER2-targeted therapy (pathologic complete response with dual-targeted therapy: 93%). (2) an immunomodulatory (HER2-IM, N=36) subtype characterized by an immune-activated microenvironment and excellent prognosis with current treatment (no relapse in 97% of patients with a median follow-up of 86 months). Tumors of this subtype were therefore candidates for de-escalatory treatment. (3) A luminal-like (HER2-LUM, N=55) subtype distinguished by activated estrogen receptor signaling and (4) a basal/mesenchymal-like (HER2-BM, N=38) subtype enriched in activated receptor tyrosine kinase pathways. HER2-LUM and HER2- BM showed limited benefit from anti-HER2 therapy, and thus, add-on therapies might be needed. The overall area under the curve (AUC) of the convolutional neural network model based on digital pathology for identifying different subtypes is 0.77. In the exploration of novel treatment strategies, we found in the PDO model that the HER2-LUM subtype is more sensitive to a treatment regimen combining standard (chemotherapy and targeted therapy) with subsequent endocrine therapy and CDK4/6 inhibitors compared to other subtypes. Additionally, the HER2-BM subtype demonstrated greater sensitivity to treatment with a combination of EGFR inhibitors, PDGFR inhibitors or VEGFR inhibitors. Conclusion: We uncovered a high degree of molecular heterogeneity in HER2-positive breast cancer and illustrated its impact on treatment response. More precise treatment can be given according to the characteristics of different subtypes, which may achieve good efficacy and simultaneously reduce overtreatment and extra cost. The comprehensive profiling of HER2-positive breast cancers could also serve as an important resource for further exploration. Key Words: HER2-positive breast cancer cohort; molecular classification; targeted therapy; precision treatment; de-escalatory treatment. Citation Format: Yu-Wei Li, Ding Ma, Xiang-Rong Wu, Lei-Jie Dai, Shen Zhao, Yu-Zheng Xu, Xi Jin, Xiao Yi, Ying Wang, Cai-Jin Lin, Yi-Fan Zhou, Tong Fu, Wen-Tao Yang, Ming Li, Hong Lv, Yi-Zhou Jiang, Zhi-Ming Shao. Multiomics profiling and molecular classification refine precision treatment strategies for HER2-positive breast cancer [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 PS09-09.

Surface modification of hollow gold nanoparticles conducted by incorporating cancer cell membrane and AS1411 aptamer, aiming to achieve a dual-targeted therapy for colorectal cancer

Due to its inherent membrane structure, a nanostructure enveloped by an active cell membrane possesses distinctive characteristics such as prolonged presence in the bloodstream, precise identification capabilities, and evasion of immune responses. This research involved the production of biomimetic nanoparticles, specifically hollow gold nanoparticles (HGNPs) loaded with methotrexate (MTX), which were further coated with cancer cell membrane. These nanoparticles were then adorned with AS1411 aptamer to serve as a targeting agent (Apt-CCM-HG@MTX). The nanoplatform demonstrated precise targeting towards cancer cells due to its dual-targeting characteristic (AS1411 aptamer and C26 cancer cell membrane), exhibiting uniformity in distribution. It also displayed a desirable response to photothermal stimulation, controlled release of drugs, and exceptional properties for fluorescence imaging. The system was composed of spherical HGNPs measuring 51.33 ± 5.70 nm in diameter, which were effectively loaded with MTX using a physical absorption method. The encapsulation efficiency achieved was recorded at 79.54 %, while the loading efficiency reached 38.21 %. The targeted formulation demonstrated a noteworthy mortality of approximately 45 % in the nucleolin positive cell line, C26, as determined by in vitro cytotoxicity assays. As a result of the functionalization process applied to the homologous binding adhesion molecules found in cancer cell membranes and targeting ability of AS1411 aptamer, Apt-CCM-HG@MTX demonstrated a substantial enhancement in targeting tumors and facilitating cellular uptake during in vivo experiments. Furthermore, under NIR radiation the photothermal effect exhibited by Apt-CCM-HG@MTX in the tumor area was notably robust due to the distinctive attributes of HGNPs. The conclusions obtained from this study have the potential to assist in adopting a bioinspired strategy that will significantly improve the effective management of MTX and therapy for individuals with colorectal cancer.

Application of Doxorubicin-loaded PLGA nanoparticles targeting both tumor cells and cancer-associated fibroblasts on 3D human skin equivalents mimicking melanoma and cutaneous squamous cell carcinoma

Nanoparticle (NP) use in cancer therapy is extensively studied in skin cancers. Cancer-associated fibroblasts (CAFs), a major tumor microenvironment (TME) component, promote cancer progression, making dual targeting of cancer cells and CAFs an effective therapy. However, dual NP-based targeting therapy on both tumor cells and CAFs is poorly investigated in skin cancers. Herein, we prepared and characterized doxorubicin-loaded PLGA NPs (DOX@PLGA NPs) and studied their anti-tumor effects on cutaneous melanoma (SKCM)(AN, M14) and cutaneous squamous cell carcinoma (cSCC) (MET1, MET2) cell lines in monolayer, as well as their impact on CAF deactivation. Then, we established 3D full thickness models (FTM) models of SKCM and cSCC using AN or MET2 cells on dermis matrix populated with CAFs respectively, and assessed the NPs' tumor penetration, tumor-killing ability, and CAF phenotype regulation through both topical administration and intradermal injection. The results show that, in monolayer, DOX@PLGA NPs inhibited cancer cell growth and induced apoptosis in a dose- and time-dependent manner, with a weaker effect on CAFs. DOX@PLGA NPs reduced CAF-marker expression and had successful anti-tumor effects in 3D skin cancer FTMs, with decreased tumor-load and invasion. DOX@PLGA NPs also showed great delivery potential in the FTMs and could be used as a platform for future functional study of NPs in skin cancers using human-derived skin equivalents. This study provides promising evidence for the potential of DOX@PLGA NPs in dual targeting therapy for SKCM and cSCC.

NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route

BackgroundEsophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC.MethodsWe isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells.ResultsOur study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157–165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast.ConclusionOur findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

Nanocarrier Design for Dual-Targeted Therapy of In-Stent Restenosis.

The injury-triggered reocclusion (restenosis) of arteries treated with angioplasty to relieve atherosclerotic obstruction remains a challenge due to limitations of existing therapies. A combination of magnetic guidance and affinity-mediated arterial binding can pave the way to a new approach for treating restenosis by enabling efficient site-specific localization of therapeutic agents formulated in magnetizable nanoparticles (MNPs) and by maintaining their presence at the site of arterial injury throughout the vulnerability period of the disease. In these studies, we investigated a dual-targeted antirestenotic strategy using drug-loaded biodegradable MNPs, surface-modified with a fibrin-avid peptide to provide affinity for the injured arterial wall. The MNPs were characterized with regard to their magnetic properties, efficiency of surface functionalization, disassembly kinetics, and interaction with fibrin-coated substrates. The antiproliferative effects of MNPs formulated with paclitaxel were studied in vitro using a fetal cell line (A10) exhibiting the defining characteristics of neointimal smooth muscle cells. Animal studies examined the efficiency of combined (physical/affinity) MNP targeting to stented arteries in Sprague Dawley rats using fluorimetric analysis and fluorescent in vivo imaging. The antirestenotic effect of the dual-targeted therapy was determined in a rat model of in-stent restenosis 28 days post-treatment. The results showed that MNPs can be efficiently functionalized to exhibit a strong binding affinity using a simple two-step chemical process, without adversely affecting their size distribution, magnetic properties, or antiproliferative potency. Dual-targeted delivery strongly enhanced the localization and retention of MNPs in stented carotid arteries up to 7 days post-treatment, while minimizing redistribution of the carrier particles to peripheral tissues. Of the two targeting elements, the effect of magnetic guidance was shown to dominate arterial localization (p = 0.004 vs. 0.084 for magnetic targeting and peptide modification, respectively), consistent with the magnetically driven MNP accumulation step defining the extent of the ultimate affinity-mediated arterial binding and subsequent retention of the carrier particles. The enhanced arterial uptake and sustained presence of paclitaxel-loaded MNPs at the site of stent deployment were associated with a strong inhibition of restenosis in the rat carotid stenting model, with both the neointima-to-media ratio (N/M) and % stenosis markedly reduced in the dual-targeted treatment group (1.62 ± 0.2 and 21 ± 3 vs. 2.17 ± 0.40 and 29 ± 6 in the control animals; p < 0.05). We conclude that the dual-targeted delivery of antirestenotic agents formulated in fibrin-avid MNPs can provide a new platform for the safe and effective treatment of in-stent restenosis.

Real-world data on neoadjuvant chemotherapy with dual-anti HER2 therapy in HER2 positive breast cancer

BackgroundNeoadjuvant chemotherapy with dual-targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)-positive breast cancer. Although the dual-targeted therapy has significantly improved the pathological complete response (pCR) rate, further investigation is needed to identify biomarkers that predict the response to neoadjuvant therapy.MethodsThis retrospective study analyzed 353 patients with HER2-positive breast invasive ductal carcinoma. The correlation between clinicopathological factors and pCR rate was evaluated. A nomogram was constructed based on the results of the multivariate logistic regression analysis to predict the probability of pCR.ResultsThe breast pCR (b-pCR) rate was 56.1% (198/353) and the total pCR (t-pCR) rate was 52.7% (186/353). Multivariate analysis identified ER status, PR status, HER2 status, Ki-67 index, and neoadjuvant chemotherapy regimens as independent indicators for both b-pCR and t-pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.73 (95% CI: 0.68–0.78). According to the nomogram, the t- pCR rate was highest in the ER-PR- HER2-positive patients (131/208) and lowest in the ER + PR + HER2-positive patients (19/73). The subgroup analyses showed that there was no significant difference in pCR rate among the neoadjuvant chemotherapy regimens in ER positive, PR positive, HER2 IHC 2 + , Ki67 index < 30% population. However, for ER-PR-HER2-positive patients, the neoadjuvant chemotherapy regimen has a great influence on the pCR rates.ConclusionsPatients with ER-negative, PR-negative, HER2 3 + and high KI-67 index were more likely to achieve pCR. THP may be used as an alternative to AC-THP or TCbHP in selected HER2-positive patients.