Chemotherapy combined with bevacizumab for small cell lung cancer with brain metastases:A case report

BACKGROUND Small cell lung cancer(SCLC)is a common and aggressive subtype of lung cancer.It is characterized by rapid growth and a high mortality rate.Approximately 10%of patients with SCLC present with brain metastases at the time of diagnosis,which is associated with a median survival of 5 mo.This study aimed to summarize the effect of bevacizumab on the progression-free survival(PFS)and overall survival of patients with brain metastasis of SCLC.CASE SUMMARY A 62-year-old man was referred to our hospital in February 2023 because of dizziness and numbness of the right lower extremity without headache or fever for more than four weeks.The patient was diagnosed with limited-stage SCLC.He received 8 cycles of chemotherapy combined with maintenance bevacizumab therapy and achieved a PFS of over 7 mo.CONCLUSION The combination of bevacizumab and irinotecan effectively alleviated brain metastasis in SCLC and prolonged PFS.

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer(NSCLC)remains the leading cause of cancer-related death in both men and women in the United States.Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease.Improvements in overall survival and quality of life have been modest.Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics,thus changing the treatment paradigm for many NSCLC patients.In this review,we present a summary of many of the currently investigated biologic targets in NSCLC,discuss their current clinical trial status,and also discuss the potential for development of other targeted agents.

Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitinproteasome pathway, epigenetic modulators, poly(ADPribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.

Role of the combination of biologics and/or small molecules in the treatment of patients with inflammatory bowel disease

Inflammatory bowel disease(IBD)is a group of chronic diseases that includes ulcerative colitis,Crohn’s disease,and indeterminate colitis.Patients with IBD require prolonged treatment and high utilization of healthcare resources for proper management.The treatment of patients with IBD is focused on achieving therapeutic goals including clinical,biochemical,and endoscopic variables that result in improvement of the quality of life and prevention of disability.Advanced IBD treatment includes tumor necrosis factor inhibitors,integrin antagonist,antagonist of the p40 subunit of interleukin 12/23,and small molecule drugs.However,despite the multiple treatments available,about 40%of patients are refractory to therapy and present with persistent symptoms that have a great impact on their quality of life,with hospitalization and surgery being necessary in many cases.Dual therapy,a strategy sometimes applicable to refractory IBD patients,includes the combination of two biologics or a biologic in combination with a small molecule drug.There are two distinct scenarios in IBD patients in which this approach can be used:(1)Refractory active luminal disease without extraintestinal manifestations;and(2)patients with IBD in remission,but with active extraintestinal manifestations or immune-mediated inflammatory diseases.This review provides a summary of the results(clinical response and remission)of different combinations of advanced drugs in patients with IBD,both in adults and in the pediatric population.In addition,the safety profile of different combinations of dual therapy is analyzed.The use of newer combinations,including recently approved treatments,the application of new biomarkers and artificial intelligence,and clinical trials to establish effectiveness during long-term followup,are needed to establish new strategies for the use of advanced treatments in patients with refractory IBD.

A Clinical and Animal Experiment Integrated Platform for Small-Molecule Screening Reveals Potential Targets of Bioactive Compounds from a Herbal Prescription Based on the Therapeutic Efficacy of Yinchenhao Tang for Jaundice Syndrome

A herbal prescription in traditional Chinese medicine(TCM)has great complexity,with multiple components and multiple targets,making it extremely challenging to determine its bioactive compounds.Yinchenhao Tang(YCHT)has been extensively used for the treatment of jaundice disease.Although many studies have examined the efficacy and active ingredients of YCHT,there is still a lack of an in-depth systematic analysis of its effective components,mechanisms,and potential targets—especially one based on clinical patients.This study established an innovative strategy for discovering the potential targets and active compounds of YCHT based on an integrated clinical and animal experiment platform.The serum metabolic profiles and constituents of YCHT in vivo were determined by ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry(UPLC-Q-ToF-MS)-based metabolomics combined with a serum pharmacochemistry method.Moreover,a compound–target–pathway network was constructed and analyzed by network pharmacology and ingenuity pathway analysis(IPA).We found that eight active components could modulate five key targets.These key targets were further verified by enzyme-linked immunosorbent assay(ELISA),which indicated that YCHT exerts therapeutic effects by targeting cholesterol 7a-hydroxylase(CYP7A1),multidrug-resistance-associated protein 2(ABCC2),multidrug-resistance-associated protein 3(ABCC3),uridine diphosphate glucuronosyl transferase 1A1(UGT1A1),and farnesoid X receptor(FXR),and by regulating metabolic pathways including primary bile acid biosynthesis,porphyrin and chlorophyll metabolism,and biliary secretion.Eight main effective compounds were discovered and correlated with the key targets and pathways.In this way,we demonstrate that this integrated strategy can be successfully applied for the effective discovery of the active compounds and therapeutic targets of an herbal prescription.

Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer(NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor(EGFR), and crizotinib which targets anaplastic lymphoma kinase(ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790 Mtargeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib(LDK378), AP26113, alectinib(CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

Inetetamab combined with pyrotinib and chemotherapy in the treatment of breast cancer brain metastasis: A case report

BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.

The “predictive molecule targeted chemotherapy” for relapsed ovarian cancer—a pilot study

Objective: How to choose chemotherapy regimen is a often-encountered and formidable problem in the setting of relapsed ovarian cancer. So far, it was usually according to the clinical trials and doctors’ experience and the response rate was very low. In the present study, we proposed a new treatment strategy–the “predictive molecule targeted chemotherapy, PMTC” to choose supposedly sensitive protocols and void supposedly resistant protocols based on the specific predictive molecule expression of individual tumor tissue. Methods: Retrospectively analysis of 16 cases of relapsed ovarian cancer patients from January 2002 to December 2003, as the experience-directed chemotherapy group (control group), to calculate the response rate. Prospectively recruit 9 cases of relapsed ovarian cancer patients after January 2004, whose chemotherapy drug choice was based on the expression of 6 predictive molecules (p53, et al) by means of immunohistochemistry, as the PMTC group, to calculate the response rate. χ2 test was used for the statistical analysis. Results: The response rate of control group was 26%, including 31% for second line and 14% for third line respectively. The response rate of PMTC group was 78%, in which 5 cases of early relapse all responded. The difference was significant (P=0.011). Conclusions: PMTC is a new effective method to treat the relapsed ovarian cancer.

Two Small Molecules, ZCL278 and AZA197 Show Promise in Influencing Protein Interactions Involving the Ras-Related Protein Cell division cycle 42 [Cdc42] to Modulate Its Oncogenic Potential

Cdc42 is a member of the Rho subfamily of Ras-related proteins, which were among the first oncogenic proteins to be identified as playing a sig-nificant role in a variety of cellular events [Barbacaid, 1987, Ann. Rev. Biochem]. Equally important, Protein-Protein Interactions [PPIs] involving Cdc42 continue to highlight the role of Ras-related proteins’ relevance to cancer. As these proteins have been considered incapable of being “druggable”, due to a perceived lack of binding surface[s] that are amenable to small molecule targeting, there remains limited development of therapies to tackle diseased states caused by Cdc42-stimulated hyperactivity. Thusly, it has become important to characterize molecular details, including dynamics, of PPIs involving Cdc42 that may lend themselves as potential targets for therapeutic approaches. Recently, two small molecules, ZCL278 and AZA197, have shown promise in directly targeting Cdc42 to influence PPIs that are capable of causing Cdc42-stimulated abnormal signaling. In this editorial, we highlight recent studies that show case how these two small molecules may influence Cdc42-protein interactions.

Missing the Target?—Targeted Therapy in Small Cell Lung Cancer

Small cell lung cancer [SCLC] is a devastating form of cancer, with most patients harbouring extensive disease at diagnosis and survival of less than 5% at five years. Progress in novel therapies has been limited. This specialist review explores current targeted therapy options and potential areas of development.

Prospective Development of Small Molecule Targets to Oncogenic Ras Proteins

Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.

Advances in research on targeted therapy for small cell lung cancer

Small cell lung cancer (SCLC) is a kind of pulmonary neuroendocrine tumor with high malignancy,rapid progression and poor prognosis.It accounts for 15% to 20% of the total number of lung cancers.Although radiotherapy and chemotherapy are better for early treatment of small cell lung cancer,they are prone to cell resistance and are prone to metastasis.With the development of targeted therapies in medical history,targeted therapies for SCLC have also received increasing attention.This article summarizes the research progress of targeted therapy in small cell lung cancer in recent years.

Treatment of non-small cell lung cancer in the era of targeted therapy

Lung cancer, mostly non-small cell carcinoma (NSCLC), is still a major global problem with devastating outcomes. The majority presents at late stages, in which the chance of cure is minimal. With the better understanding of lung cancer biology, there have been several novel targeted approaches against NSCLC. Anti-angiogenesis has been proven to be an important approach in combination with systemic chemotherapy treatment in NSCLC at the first-line setting. The prototypic monoclonal antibody against vascular endothelial growth factor (VEGF), be- vacizumab, is now approved for clinical use in combination with platinum-based chemotherapy in first-line treatment of advanced non-squamous NSCLC, associated with improved response and survival compared with chemotherapy alone. The most notable example of targeted therapy for lung cancer is epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI). There have been extensive evidences supporting the superiority of EGFR TKI (like gefitinib or erlotinib) over standard platinum-based doublet chemotherapy in first-line treatment of advanced NSCLC carrying EGFR activating mutations. Almost following the same path as EGFR TKI, a novel target (anaplastic lymphoma kinase, ALK) has been identified recently with a very promising targeted agent (crizotinib) that has already been approved for clinical use in NSCLC carrying ALK rearrangements. Over the past decade, there have been undoubtedly growing armamentaria in the treatment of NSCLC, focusing on personalized and targeted approach.

New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers

Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy,including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin,Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.

Targeted therapies for patients with advanced NSCLC harboring wild-type EGFR:what's new and what's enough

Historically,non-small cell lung cancer(NSCLC) is divided into squamous and nonsquamous subtypes based on histologic features.With a growing number of oncogenic drivers being identified in squamous and nonsquamous NSCLC,this malignancy has been recently divided into several distinct subtypes according to the specific molecular alterations.This new paradigm has substantially highlighted the treatment of advanced NSCLC,shifting it from standard chemotherapy according to specific histologic subtypes to targeted therapy according to specific oncogenic drivers.The application of epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs) in NSCLC patients harboring activating EGFR mutations has been a representative model of precise medicine in the treatment of NSCLC.As the role of EGFR-TKIs in routine management of patients with advanced NSCLC has been well established,this review provides an overview of alternative targeted therapy in the treatment of NSCLC,including EGFR-TKIs for patients with wild-type EGFR NSCLC,as well as other targeted agents either clinical available or in early- to late-stage development.

2023年度非小细胞肺癌外科治疗进展

肺癌是当前世界各地最普遍和最致命的癌症,严重威胁人们的生命健康。外科手术切除是最早治疗肺癌的手段,也是目前肺癌最主要的治疗手段。随着医学技术的进步,外科手术方法和辅助治疗策略不断革新,这为肺癌患者带来了新的希望。因此总结肺癌外科治疗领域的最新研究进展具有重要意义。本文旨在综述2023年度非小细胞肺癌(non-small cell lung cancer,NSCLC)外科治疗的主要进展,包括手术技术的创新、微创手术、辅助分子靶向治疗及免疫治疗在NSCLC围手术期的应用等。

多靶点小分子酪氨酸激酶抑制剂联合免疫检查点抑制剂治疗标准治疗方案失败后晚期实体瘤患者的效果

目的研究多靶点小分子酪氨酸激酶抑制剂(MTKIs)和免疫检查点抑制剂(ICIs)联合治疗对标准治疗方案失败的晚期实体瘤患者的临床疗效与安全性。方法选择2021年1月至2023年1月在我院住院的≥2个标准治疗方案失败后的晚期实体瘤患者,采用了MTKIs联合ICIs的治疗方案,回顾性研究该方案的疗效与安全性。结果共纳入21例患者,截至2023年3月1日,整体人群ORR为38%,DCR为67%,中位无进展生存期(mPFS)为10个月,中位生存期(mOS)为15个月。常见的不良反应为肺炎、口腔溃疡等。结论对于标准治疗失败的晚期实体瘤患者,MTKIs和ICIs联合治疗方法可能是一种治疗选择,但需要更大样本量的前瞻性研究证实其疗效及安全性,以及探索出最有可能从这种治疗方法中获益的人群。

系统性硬皮病靶向治疗研究进展

系统性硬皮病(SSc)作为一种免疫介导的慢性结缔组织疾病,以皮肤、肺等多器官纤维化为主要临床表现,属于罕见病范畴,但发病率和死亡率在风湿免疫性疾病中均排在前列。目前尚无有效的治疗药物。近年来研究发现,T/B淋巴细胞、成纤维细胞、内皮细胞等相互作用及各种促炎促纤维化信号分子激活在其发生发展中起着关键性作用,在此基础上正在研发系列靶向药物。其中靶向B细胞耗竭的CD20单克隆抗体(利妥昔单抗)、IL-6受体拮抗剂(托珠单抗)、多靶点酪氨酸激酶抑制剂(尼达尼布)等在国际上已被批准用于SSc或系统性硬化病相关间质肺疾病(SSc-ILD)治疗;其他靶向药物如Janus激酶抑制剂、多种白介素抑制剂等在临床试验阶段,部分展现初步应用前景。本文从靶向B淋巴细胞、T淋巴细胞、血管内皮细胞及促炎促纤维化信号分子4个方面综合最新证据,就靶向疗法在SSc中的研究进展进行综述。

放射治疗联合靶向疗法对非小细胞肺癌晚期患者临床有效性研究

目的 研究放射治疗联合靶向疗法对非小细胞肺癌(Non-Small Cell Lung Cancer, NSCLC)晚期患者的临床有效性。方法 方便选取2022年6月—2023年6月山东省淄博市中心医院收治的96例非小细胞肺癌晚期患者为研究对象,采用随机数表法分为对照组和观察组,每组48例。对照组采用放射治疗,观察组采用放射治疗联合靶向疗法。比较两组疗效、肿瘤标志物、免疫功能、不良反应发生率。结果 观察组缓解率(56.25%)和疾病控制率(87.50%)高于对照组(35.42%、68.75%),差异有统计学意义(χ^(2)=4.196、4.937,P均<0.05)。治疗后,观察组细胞角蛋白19片段、癌胚抗原、糖类抗原199、CD8^(+)水平均低于对照组,CD4^(+)、CD3^(+)水平高于对照组,差异有统计学意义(P均<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论 放射治疗联合靶向疗法对非小细胞肺癌晚期患者治疗效果高,可获得更高的控制率,能有效下调细胞角蛋白19片段、癌胚抗原、糖类抗原199水平,调节免疫,且不增加不良反应。