更新于：2024-04-01

Rhabdomyosarcoma

横纹肌肉瘤

更新于：2024-04-01

基本信息

别名

Malignant soft tissue tumor of skeletal muscle differentiation、Malignant soft tissue tumour of skeletal muscle differentiation、RHABDOMYOSARCOMA

+ [24]

简介

A malignant solid tumor arising from mesenchymal tissues which normally differentiate to form striated muscle. It can occur in a wide variety of sites. It is divided into four distinct types: pleomorphic, predominantly in male adults; alveolar (RHABDOMYOSARCOMA, ALVEOLAR), mainly in adolescents and young adults; embryonal (RHABDOMYOSARCOMA, EMBRYONAL), predominantly in infants and children; and botryoidal, also in young children. It is one of the most frequently occurring soft tissue sarcomas and the most common in children under 15. (From Dorland, 27th ed; Holland et al., Cancer Medicine, 3d ed, p2186; DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, pp1647-9)

关联

项与横纹肌肉瘤相关的药物

Teprotumumab-TRBW

替妥木单抗

靶点

IGF-1R

作用机制

IGF-1R拮抗剂

在研机构

Horizon Therapeutics USA, Inc. [+1]

原研机构

Genmab A/S

在研适应症

格雷夫斯眼病

非在研适应症

晚期癌症 [+12]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2020-01-21

Sonidegib Phosphate

磷酸索立德吉

靶点

SMO

作用机制

SMO拮抗剂

在研机构

Sun Pharmaceutical Industries (Europe) BV [+3]

原研机构

Novartis Pharma AG

在研适应症

基底细胞癌 [+16]

非在研适应症

急性白血病 [+39]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2015-07-24

Nivolumab

纳武利尤单抗

靶点

PD-1

作用机制

PD-1抑制剂

在研机构

Bristol Myers Squibb Co. [+14]

原研机构

Ono Pharmaceutical Co., Ltd. [+1]

在研适应症

皮肤肿瘤 [+244]

非在研适应症

获得性免疫缺陷综合征 [+67]

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期2014-07-04

265

项与横纹肌肉瘤相关的临床试验

NCT06198296 / Not yet recruiting临床1期IIT

Immunotherapy For Adults With GPC3-Positive Solid Tumors Using Interleukin-15 And -21 Armored Glypican-3-Specific Chimeric Antigen Receptor Expressing Autologous T Cells

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells.
Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise but have not been strong enough to cure most patients.
In order to get them to kill cancers more effectively, in the laboratory, the study team inserted a new gene called a chimeric antigen receptor (CAR) into T cells that makes them recognize cancer cells and kill them. When inserted, this new CAR T cell can specifically recognize a protein found on solid tumors, called glypican-3 (GPC3). To make this GPC3-CAR more effective, the study team also added two genes called IL15 and IL21 that help CAR T cells grow better and stay in the blood longer so that they may kill tumors better. When the study team did this in the laboratory, they found that this mixture of GPC3-CAR,IL15 and IL21 killed tumor cells better when compared with CAR T cells that did not have IL15 plus IL21 in the laboratory. This study will use those cells, which are called 21.15.GPC3-CAR T cells, to treat patients with solid tumors that have GPC3 on their surface.
The study team also wanted to make sure that they could stop the 21.15.GPC3-CAR T cells from growing in the blood should there be any bad side effects. In order to do so, they inserted a gene called iCasp9 into the FAST-CAR T cells. This allows us the elimination of 21.15.GPC3-CAR T cells in the blood when the gene comes into contact with a medication called AP1903. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. This drug will only be used to kill the T cells if necessary due to side effects .
The study team has treated patients with T cells that include GPC3. Patients have also been treated with IL-21 and with IL-15. Patients have not been treated with a combination of T cells that contain GPC3, IL-21 and IL-15. To summarize, this study will test the effect of 21.15.GPC3-CAR T cells in patients with solid tumors that express GPC3 on their surface.
The 21.15.GPC3-CAR T cells are an investigational product not yet approved by the Food and Drug Administration.

开始日期2026-01-01

申办/合作机构

Baylor College of Medicine

[+1]

NCT06029465 / Not yet recruitingN/A

Analyzing Engagement Trends in Rhabdomyosarcoma Clinical Trials: A Study of Participation Patterns Among Those Affected by the Disorder

The study seeks to delve into the firsthand experiences of patients diagnosed with rhabdomyosarcoma who partake in a separate clinical trial featuring a specific medical intervention. The primary emphasis will be on meticulously tracking the rates of trial completion and withdrawal among these individuals.
The data collected from this study will help improve future outcomes for all rhabdomyosarcoma patients as well as those in under-represented demographic groups.

开始日期2024-10-01

申办/合作机构

Power Life Sciences, Inc.初创企业

NCT04890093 / Not yet recruiting临床1/2期IIT

Phase 1/2 Study of Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors

Background:
The drug PEN-866 can remain in tumor cells longer than it does in normal cells. It also may be more effective than other drugs at treating Ewing sarcoma and rhabdomyosarcoma. Researchers want to learn if combining PEN-866 with other drugs can treat certain cancers in adolescents and young adults.
Objective:
To learn if the combination of PEN-866 with vincristine and temozolomide can be used to treat adolescents and young adults with solid tumors that have returned after or did not respond to standard treatments, or for which there are no standard treatments.
Eligibility:
People ages 12-39 years who have solid tumors, Ewing sarcoma, or rhabdomyosarcoma that returned after or did not respond to standard treatments.
Design:
Participants will be screened with a medical history, physical exam, and eye exam. They will have heart function tests. They may have imaging scans of the chest, abdomen, and pelvis. They will give blood and urine samples. They may have a tumor biopsy. Some samples will be used for genetic testing. Some screening tests will be repeated during the study.
Participants will get 3 drugs for up to 18 cycles. Each cycle lasts 21 days. They will get PEN-866 and vincristine by IV infusion (a tube in their vein) on Days 1 and 8 of each cycle. They will take temozolomide by mouth on Days 1-5 of each cycle.
Participants will complete questionnaires about their physical, mental, and social health.
Participants will have a follow-up visit 30 days after treatment ends. They may be contacted by phone or email for the rest of their life.

开始日期2024-04-03

申办/合作机构

National Cancer Institute

100 项与横纹肌肉瘤相关的临床结果

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100 项与横纹肌肉瘤相关的转化医学

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0 项与横纹肌肉瘤相关的专利（医药）

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12,249

项与横纹肌肉瘤相关的文献（医药）

2024-03-01·Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

The Role of Motion Sensitivity and Headaches on Vestibular Rehabilitation Outcomes in Pediatric Vestibular Migraines.

Article

作者: Adam S Vesole ; Katheryn R Bachmann ; Gretchen A Mueller ; Violette H Lavender ; Micheal Castiglione ; John H Greinwald

OBJECTIVE:

To determine the utility of the motion sensitivity quotient (MSQ) in diagnosing pediatric vestibular migraine (VM) and to characterize the role of motion sensitivity and headache control on vestibular rehabilitation (VR) outcomes in pediatric VM.

STUDY DESIGN:

Retrospective cohort analysis.

SETTING:

Pediatric tertiary referral center.

PATIENTS:

Children (≤18 years old) with dizziness who completed vestibular testing from January 2016 to August 2022, diagnosed with either VM or another vestibular disorder.

INTERVENTIONS:

VR, which included MSQ testing.

MAIN OUTCOME MEASURES:

Initial MSQ, number and duration of vestibular physical therapy (PT) sessions, PT goals met, and posttreatment MSQ.

RESULTS:

Two hundred fifty-seven patients met study criteria. MSQ was not a reliable diagnostic marker in pediatric VM as there was no difference in initial MSQ between VM and non-VM patients (9.4 vs. 7.8 in non-VM, p = 0.014). Both VM (n = 116) and non-VM (n = 141) patients demonstrated significant improvement in MSQ after VR (p = 0.004). However, VM patients tended to be less likely to meet at least one PT goal (60 vs. 77% in non-VM, p = 0.016, d = 0.37), although not significant. VM patients with more frequent headaches had significantly higher initial MSQ (p = 0.008). VM patients with more frequent headaches or higher initial MSQ tended to require increased number and longer duration of VR (small/medium effect size although not statistically significant after Bonferroni correction).

CONCLUSION:

VR is an effective treatment for both VM and non-VM pediatric patients. VM patients, especially those with severe motion sensitivity or poorly controlled headaches, may be less responsive to VR and may require increased frequency and duration of VR. Our findings propose the importance of counseling pediatric patients with severe motion sensitivity or uncontrolled migraines regarding realistic expectations of their VR course.

2024-03-01·Radiographics : a review publication of the Radiological Society of North America, Inc

Biliary Disorders, Anomalies, and Malignancies in Children.

Article

作者: Curtis L Simmons ; Laura K Harper ; Mittun C Patel ; Venkat S Katabathina ; Richard N Southard ; Luis Goncalves ; Evelyn Tran ; Deepa R Biyyam

Biliary abnormalities in children are uncommon, and the spectrum of biliary disorders is broader than in adult patients. Unlike in adults, biliary disorders in children are rarely neoplastic and are more commonly rhabdomyosarcoma rather than cholangiocarcinoma. Pediatric biliary disorders may be embryologic or congenital, such as anatomic gallbladder anomalies, anomalous pancreaticobiliary tracts, various cholestatic processes, congenital cystic lesions, or genetic conditions. They may also be benign, such as biliary filling anomalies, biliary motility disorders, and biliary inflammatory and infectious disorders. Distinguishing these entities with a single imaging modality is challenging. US is the primary imaging modality for initial evaluation of biliary abnormalities in children, due to its wide availability, lack of ionizing radiation, and low cost and because it requires no sedation. Other examinations such as MRI, CT, and nuclear medicine examinations may provide anatomic and functional information to narrow the diagnosis further. Hepatobiliary-specific contrast material with MRI can provide better assessment of biliary anatomy on delayed images than can traditional MRI contrast material. MR cholangiopancreatography (MRCP) allows visualization of the intra- and extrahepatic biliary ducts, which may not be possible with endoscopic retrograde cholangiopancreatography (ERCP). Suspected biliary atresia requires multiple modalities for diagnosis and timely treatment. Determining the type of choledochal cyst calls for a combination of initial US and MRCP. Many benign and malignant biliary masses require biopsy for definitive diagnosis. Knowledge of the imaging appearances of different pediatric biliary abnormalities is necessary for appropriate imaging workup, providing a diagnosis or differential diagnosis, and guiding appropriate management. ^©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

2024-02-24·Nature communications

KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma.

Article

作者: Yong Yean Kim ; Berkley E Gryder ; Ranuka Sinniah ; Megan L Peach ; Jack F Shern ; Abdalla Abdelmaksoud ; Silvia Pomella ; Girma M Woldemichael ; Benjamin Z Stanton ; David Milewski ; Joseph J Barchi ; John S Schneekloth ; Raj Chari ; Joshua T Kowalczyk ; Shilpa R Shenoy ; Jason R Evans ; Young K Song ; Chaoyu Wang ; Xinyu Wen ; Hsien-Chao Chou ; Vineela Gangalapudi ; Dominic Esposito ; Jane Jones ; Lauren Procter ; Maura O'Neill ; Lisa M Jenkins ; Nadya I Tarasova ; Jun S Wei ; James B McMahon ; Barry R O'Keefe ; Robert G Hawley ; Javed Khan

Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.

159

项与横纹肌肉瘤相关的新闻（医药）

2024-03-26

·今日头条

“双靶点”CAR-T强势来袭，2天内肿瘤奇迹缩小！CAR-T重击实体瘤

2024年伊始，CAR-T研发领域不断传来好消息，近日世界权威期刊《自然医学（nature medicine）》上，报道了首次使用双靶点CAR-T细胞（即CART-EGFR-IL13Rα2细胞）治疗胶质母细胞瘤（GBM），显示出初步活性和安全性，在治疗短短2天内，MRI就已出现肿瘤缩小表现，这意味着CAR-T在治疗实体瘤的有效性、持久性方面再进一层楼，攻克实体瘤指日可待！ ▲截图源自“nature medicine” 双靶点CAR-T具有强大抗肿瘤活性，治疗2天内肿瘤奇迹般缩小 CAR-T细胞疗法已获FDA批准，用于治疗多种血液系统恶性肿瘤。近年来，研究人员一直在努力研发并提升CAR-T细胞，用于对抗各类实体瘤。本次应用的“双靶点”CAR-T细胞，打破了传统CAR-T只具有单一靶点的局限性，针对脑肿瘤常见的两种相关蛋白，即表皮生长因子受体（ EGFR ，存在于约60%的胶质母细胞瘤中）、白细胞介素13受体α2 （ IL13Rα2 ，存在于约75%的胶质母细胞瘤中），进行研发。在1期试验（NCT05168423）中，纳入6例复发性胶质母细胞瘤患者，采用鞘内注射的方式，对患者施用这款“EGFR”和“IL13Rα2”双靶点CAR-T细胞（即CART-EGFR-IL13Rα2）后， 24~48小时复查MRI显示，所有6例患者的肿瘤体积均缩小（详见下图），而且部分患者缩小状态维持数月。此外，神经毒性也在可控范围内。图1 一例胶质母细胞瘤患者治疗前后MRI变化 ▲图源“Penn Medicine News”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除综上，CART-EGFR-IL13Rα2细胞在治疗复发性胶质母细胞瘤方面，具有初步的安全性及生物活性。全球肿瘤医生网小编会持续关注后续研究报道，也期望它能早日上市惠及更多的患者。其实除了这款新型双靶点CAR-T细胞外，还有多款CAR-T细胞在实体瘤治疗领域，获得了不俗的疗效，下面简单盘点一下，以供参考。国研GPC3 CAR-T细胞，晚期肝细胞癌患者无瘤生存超7年 ▲截图源自“WILEY Online Library” 国际知名期刊《Cancer Communications（癌症通讯）》，介绍了1例晚期肝细胞癌患者，在接受国研创新——CAR-GPC3 T细胞治疗后，完全缓解长达7年的报道，引起了巨大轰动！这位54岁的男性肝细胞癌患者，既往接受过手术治疗，但效果不佳，术后3个月后癌症复发，在多次治疗后，出现下腔静脉癌栓、腹膜后淋巴结转移等表现。此时对他而言，临床已无更好的治疗方案。抱着最后的希望，他参加了中国进行的CAR-GPC3 T细胞临床试验。这款CAR-T细胞针对的是肝细胞癌中名为“GPC3”的癌胚抗原， GPC3因其在70%~80%的肝细胞癌中高表达，而在正常组织中几乎不表达，因而被认为是精准治疗肝癌细胞的“黄金”靶标！该患者在入组接受CAR-T细胞联合局部治疗2周后，达到了完全缓解（详见下图）。幸运的是，截至目前他已实现7年以上无瘤生存。值得一提的是，在此期间，该患者除口服抗乙型肝炎病毒（HBV）药物治疗外，并未接受其他抗癌治疗。 CAR-T 疗法招募进行时：目前有多款CAR-T临床实验正在进行中，主要针对以下癌种： Claudin18.2 ：用于治疗胃癌，胰腺癌等；间皮素（mesothelin）：用于治疗间皮瘤、胰腺癌、卵巢癌、肺癌； CEA ：用于治疗肺癌、结肠癌、胃癌、乳腺癌和胰腺癌； MUC-1 ：用于治疗肝癌、肺癌、胰腺癌、结肠癌、胃癌; GPC3：用于治疗肝癌; GUCY2C ：用于治疗结直肠癌； PSMA ：用于治疗前列腺癌等； EGFＲvII ：用于治疗神经胶质瘤、头颈部肿瘤； B7-H3 ：用于治疗尤文肉瘤、横纹肌肉瘤、肾母细胞瘤、神经母细胞瘤、髓母细胞瘤、特别难以治疗的脑干肿瘤（DIPG）。上述癌种患者如果想检测相关靶点或寻求CAR-T疗法帮助，可提交资料至全球肿瘤医生网医学部进行初步评估。国研CT041宣战胰腺癌，肿瘤大幅缩小 ▲截图源自“BMC”网站 2023年11月，《血液学与肿瘤学杂志》报道了一例转移性胰腺癌患者，在接受国研CT041治疗后，靶病灶和转移灶明显缩小的的案例。该患者为58岁女性，既往接受标准治疗失败，肿瘤持续进展，已发生全身转移。万念俱灰下，她入组接受了CT041细胞回输治疗。这是一款针对 CLDN18.2（即Claudin18.2，在胰腺癌中高表达）的新型CAR-T细胞产品，既往在治疗消化系统恶性肿瘤中获得了良好的缓解率。该患者在CT041治疗后，幸运的达到部分缓解（PR），靶病灶显著缩小30%以上，同时肺转移也出现了大幅缩小（详见下图）！图患者治疗前后肺部影像学评估 ▲图源“BMC”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除注;“★”表示“原发病变”。 CAR-T在其他实体瘤治疗领域大放异彩 PART1 晚期铂耐药卵巢癌，PRGN-3005治疗后疾病控制率高达85.7% PRGN-3005是一种Ultra CAR-T细胞疗法，用于治疗晚期复发性卵巢癌、输卵管癌、原发性腹膜癌等。《临床肿瘤学杂志》发表了“PRGN-3005治疗复发或难治性卵巢癌”的1/1b期临床研究结果，在入组的25例可评估患者中，其中位年龄为64岁(38-76)，既往接受过8种治疗方案的大量预处理。将这些患者分为三组，即环磷酰胺LD治疗组（IVLD，n=7）、经腹膜内(IP)输注组（C1，n=12）、经静脉(IV)输注组（C2，n=6）。结果显示，IVLD组患者首次再分期时的疾病控制率(DCR)高达85.7%，CA125平均降低了27.4% ，靶肿瘤负荷降低57% (4/7)。在接受第二次PRGN-3005回输治疗后，1例患者的目标肿瘤负荷减少28% 。且未发生与PRGN-3005相关的严重不良反应，如≥3级细胞因子释放综合征(CRS)、神经毒性、剂量限制性毒性等。综上，PRGN-3005 Ultra CAR-T细胞疗法，在治疗卵巢癌中获得了较为理想的疾病控制率（DCR）率，且耐受性良好、总体肿瘤负荷减少。 PART2 结直肠癌：GCC19CART治疗后，客观缓解率达50% GCC19CART是由上海斯丹赛生物公司研发的一款CAR-T细胞产品，已获得美国食品和药物管理局（FDA）授予的快速通道资格，用于治疗结直肠癌。根据实体肿瘤疗效评价标准，13例1级剂量组患者的客观缓解率（ORR）达15.4% (2/13)，8例2级剂量组患者的 ORR达50% (4/8)！小编寄语美国生物学家乔治•戴利曾说过：“如果说20世纪是药物治疗的时代，那么21世纪就是细胞治疗的时代”。随着医学技术的不断发展，以过继性免疫细胞治疗、癌症疫苗等为代表的肿瘤免疫疗法，也成了继手术、放疗、化疗后的第四种肿瘤治疗方法。其中就不得不提到获得突破性进展的CAR-T细胞疗法，随着多款产品相继获批上市，CAR-T进入井喷式的发展模式。目前国内共有24家企业布局CAR-T疗法，包括驯鹿医疗、传奇生物、复星凯特科济生物、药明巨诺、信达生物、西比曼生物等。研究人员也在不断探索新的靶点、甚至开发双靶点，以尝试用于多款实体瘤的治疗。全球肿瘤医生网小编也希望在各国专家的共同努力下，CAR-T细胞可以早日突破价格和实体瘤的瓶颈，让更多晚期癌症患者受益！参考资料 [1]Bagley SJ,et al.Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nat Med. 2024 Mar 13. https://www.nature.com/articles/s41591-024-02893-z [2]Qi C,et al.CT041 CAR T cell therapy for Claudin18.2-positive metastatic pancreatic cancer. J Hematol Oncol.2023 Sep 9;16(1):102. https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01491-9 [3]https://www.pennmedicine.org/news/news-releases/2024/march/dual-target-cell-therapy-appears-to-shrink-brain-tumors

细胞疗法免疫疗法临床1期信使RNA

2024-03-14

·Pharmaceutical Technology

FDA approves Mirum’s LIVMARLI for cholestatic pruritus

Mirum Pharmaceuticals’s LIVMARLI (maralixibat) oral solution is now available in the US for cholestatic pruritus in patients with PFIC. Credit: Mirum Pharmaceuticals / Business Wire. The US Food and Drug Administration (FDA) has approved Mirum Pharmaceuticals ’s LIVMARLI (maralixibat) oral solution to treat cholestatic pruritus. The medication is intended for patients aged five years and above with progressive familial intrahepatic cholestasis (PFIC). A once-daily, orally administered ileal bile acid transporter inhibitor, LIVMARLI is the sole FDA-approved treatment for PFIC. The approval is based on findings from the Phase III MARCH clinical trial in 93 PFIC patients. The randomised trial enrolled people with PFIC genetic types PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6, along with people with unidentified mutational status. See Also: Terns scores FDA orphan designation for CML therapy FDA issues CRL to Mapi Pharma for GA Depot to treat RMS The FDA, the European Commission and Health Canada have also granted approval for LIVMARLI for the treatment of cholestatic pruritus in patients with Alagille syndrome in their respective regions. In addition to its current approvals, Mirum has filed a supplemental new drug application to the FDA. The aim is to introduce a higher concentration formulation of LIVMARLI, which was utilised in the Phase III MARCH study. This could expand the treatment’s label for younger PFIC patients later in 2024. A rare genetic disorder, PFIC results in progressive liver disease that can go on to cause liver failure. Mirum Pharmaceuticals CEO Chris Peetz stated: “LIVMARLI has the potential to have a transformational impact for patients with cholestatic pruritus associated with PFIC, and importantly, offers an option for those patients with the rarest of subtypes. “Thank you to the patients, families and clinicians whose study participation made this approval possible.” In September 2023, the company concluded the acquisition of the bile acid product portfolio of Travere Therapeutics . Mirum gained the rights and assets related to Cholbam (cholic acid) and Chenodal (chenodiol). Travere secured $210m from Mirum, with the potential to receive $235m in sales-based milestone payments.

上市批准孤儿药临床结果临床3期并购

2024-03-12

·精准药物

【Nature子刊】靶向FGFR的抑制剂、耐药和新方向

前言成纤维细胞生长因子（FGF）通过FGF受体（FGFR1-4）发出信号，协调胎儿发育，有助于组织和全身稳态，但FGFR基因的融合、重排或突变也可能促进肿瘤发生。FGFR融合可分为I型（非受体型，由融合伴侣的N端置换引起，如BCR-FGFR1和ZYM2-FGFR1）、IIa型（受体型，也由融合伴侣N端置换产生；如FN1-FGFR1、KLK2-FGFR2）或IIb型（受体型，由融合伴侣C端置换产生；如FGFR2-BICC1、FGFR3-TACC3）。在实体瘤中检测到的FGFR变化包括非小细胞肺癌中的FGFR1扩增（20%）、乳腺癌中的FGFR 1/2扩增（7-23%）、尿路上皮癌中的FGFR3突变（10-60%）或FGFR3融合（6%）、肝内胆管癌中的FGFR2融合（10-20%）、子宫内膜癌中的FGFR2突变（12%）和胃癌中FGFR2的扩增（5-10%）。在约7.0%的未经选择的癌症患者中可以检测到FGFR基因的改变。目前，已经开发出了多种FGFR靶向药物，包括泛FGFR抑制剂（erdafitinib和futibatinib）、FGFR1/2/3抑制剂（infigratinib和pemigatinib），以及一系列更具特异性的药物，其中一些已进入临床使用。Erdafitinib已被批准用于携带FGFR2/3突变的尿路上皮癌患者，futibatinib和pemigatinib被批准治疗携带FGFR2融合或重排的胆管癌患者。这些药物的临床益处在一定程度上受到高磷血症的限制，这是由于FGFR1的脱靶抑制以及FGFR基因中耐药性突变的出现。下一代小分子抑制剂，如lirafugratinib和LOXO-435，以及FGFR2特异性抗体bemarituzumab，有望降低高磷血症的风险，并有能力克服某些耐药性突变。FGFR的结构和信号通路FGFs由具有球状或非典型β三叶结构的保守核心结构域组成，可分为典型FGFs（FGF1-10、FGF16-18、FGF20和FGF22）、内分泌型FGF（FGF19/FGF15、FGF21和FGF23）以及FGF同源因子（FGF11-14）。全长FGF受体（FGFR1-4）是I型跨膜蛋白，具有三个细胞外免疫球蛋白样结构域和一个胞内酪氨酸激酶结构域。典型的FGF与硫酸乙酰肝素辅因子一起通过FGFR传递信号，而内分泌型FGF与klotho共受体（KLA和KLB）和硫酸乙酰肝素辅助因子一起通过FGFR传递信号。FGF–FGFR信号传导参与细胞存活、增殖、代谢、迁移和分化，包括生理作用，如协调胎儿发育和维持组织和/或全身稳态。这些受体也可以驱动肿瘤的发展。FGFR中配体依赖性二聚化或病理改变通过自身抑制机制释放而导致内源性激酶激活。FGFR激活导致FRS2依赖性激活PI3K–AKT、RAS–ERK和磷脂酶Cγ（PLCγ）依赖性二酰基甘油（DAG）–PKC和IP3–Ca2+信号。癌症患者的FGFR改变通过异常的FGFR信号传导促进肿瘤发生：FGFR扩增导致FGFR过度表达和下游信号通路过度激活；FGFR融合或重排导致融合伴侣介导的FGFR二聚化、磷酸化改变和异常的下游信号传导；细胞外区或跨膜结构域中的FGFR突变通过改变对FGF配体的特异性或亲和力，以及配体非依赖性二聚化来激活FGFR；酪氨酸激酶结构域中的FGFR突变由于自身抑制机制的破坏而结构性性地激活FGFR。小分子FGFR抑制剂几种小分子FGFR抑制剂已被开发用于治疗具有FGFR改变的癌症患者，如尿路上皮癌、乳腺癌、胃癌、肝癌、肺癌、卵巢癌和宫颈癌。能够与酪氨酸激酶结构域的ATP结合位点结合的FGFR抑制剂通常分为多激酶FGFR抑制剂或选择性FGFR抑制剂。Derazatinib、dovitinib、tasurgratinib、lenvatinib、lucitanib、nintedanib和ponatinib都是多激酶FGFR抑制剂，对FGFR以外的多种RTK具有活性。然而，由于其广泛的活性，与选择性FGFR抑制剂相比，多激酶FGFR抑制剂的作用机制和不良反应都很复杂。选择性FGFR抑制剂包括泛FGFR、FGFR1/2/3和FGFR2/3抑制剂以及选择性FGFR2、FGFR3或FGFR4抑制剂。泛FGFR抑制剂包括 erdafitinib, futibatinib, rogaratinib和resigratinib；FGFR1/2/3抑制剂包括pemigatinib, infigratinib, fexagratinib和zoligratinib；Lirafugratinib是一种选择性FGFR2抑制剂，LOXO-435是一种选择FGFR3抑制剂，roblitinib和fissotioninib是选择性FGFR4抑制剂。目前，根据在II期试验中观察到的疗效和耐受性，美国食品药品监督管理局（FDA）在这些适应症的二线或更后线的治疗中加速批准erdafitinib、futibatinib、infigratinib和pemiginib。在erdafitinib的临床研究（BLC2001）中，根据FGFR3或FGFR2/FGFR3融合物中至少一种突变的存在，选择局部晚期和/或不可切除的尿路上皮癌患者。整体队列的ORR为40%，中位无进展生存期（mPFS）和中位总生存期（mOS）分别为5.5个月和13.8个月。46%的患者出现≥3级不良事件，在初步分析中包括低钠血症（11%）、口腔炎（10%）和乏力（7%），以及长期随访的指甲（15%）、口炎（14%）和皮肤事件（8%）。在FIGHT-203的II期研究中，在携带I型FGFR1融合（如ZMYM2–FGFR1或BCR–FGFR2）的MLN患者中测试了pemiginib的药效和安全性。其中77%（24/31）的患者对pemiginib有完全响应。常见的≥3级不良事件包括贫血（18%）、口腔炎和四肢疼痛（均为12%）。2022年8月，FDA批准了pemiginib用于携带FGFR1融合的复发性和/或难治性MLN患者。任何级别的高磷血症都发生在大多数接受泛FGFR抑制剂或FGFR1/2/3抑制剂的患者中。这种不良反应很可能反映了泛FGFR或FGFR1/2/3抑制剂对FGF23信号传导的抑制，因为这种分泌蛋白依赖于与近端小管上皮细胞膜上的FGFR1和klotho的结合。该复合物通过抑制磷酸钠协同转运蛋白（NPT2a/c）调节肾脏中的磷酸盐吸收。FGFR1在这一过程中的作用得到证实，因此，开发FGFR2特异性和FGFR3特异性抑制剂有望避免或降低这种不良反应的发生率。FGFR抑制性单克隆抗体在靶向FGF/FGFR信号的生物制剂中，bemarituzumab是目前正在III期试验中评估的唯一药物。bemarituzumab是一种人源化抗FGFR2b抗体，其抑制FGF7、FGF10和FGF22的结合，从而抑制癌细胞中配体诱导的FGFR2b信号传导，并且由于修饰的Fc结构域对自然杀伤细胞上的人FcγRIIIA受体的亲和力增加，因此具有诱导抗体依赖性细胞介导的细胞毒性（ADCC）的能力。在一项涉及晚期FGFR2b过表达胃和胃食管交界腺癌（GEA）患者的I期试验中，bemarituzumab单药治疗显示出可接受的耐受性，ORR为18%（5/28）。随后，在携带FGFR2扩增或FGFR2过表达的GEA患者的II期FIGHT试验中，将bemarituzumab与mFOLFOX6（包括氟嘧啶、亚叶酸和奥沙利铂）联合测试。bemarituzumab联合化疗组和安慰剂联合化疗组患者的ORR分别为53%和40%，mPFS分别为9.5个月和7.4个月（P=0.073)。bemarituzumab的其他几项试验，包括评估bemarituzumab联合mFOLFOX6加(NCT0511626) 或不加(NCT050252801) nivolumab在先前未经治疗的晚期GEA患者中的研究正在进行中。新型FGFR靶向疗法蛋白水解靶向嵌合体（PROTAC）、嵌合抗原受体（CAR）T细胞、抗体偶联药物（ADC）、放射免疫偶联物（RICs）和可溶性受体是能够靶向FGF–FGFR信号级联的潜在新治疗模式，其中一些已经或正在临床试验中进行测试。PROTACPROTAC具有双重部分，使其能够与靶蛋白和E3泛素连接酶相互作用，从而诱导靶蛋白的泛素化介导的蛋白酶体降解。LC-MB12是一种基于infigratinib的PROTAC，能够优先降解FGFR2，并抑制表达TEL–FGFR2融合的Ba/F3细胞和FGFR2扩增的SNU16癌细胞的增殖。相比之下，DGY-09-192是另一种基于 infigratinib的PROTAC，旨在募集von Hippel–Lindau蛋白（VHL），从而优先降解FGFR1和FGFR2。这些药物目前仍处于临床前开发阶段。CAR-T细胞由于PAX3–FOXO1的下游作用，FGFR4在儿科横纹肌肉瘤中普遍过表达。然而，N535K和V550L等耐药性突变通常在治疗前出现，这可能会限制小分子抑制剂的有效性。因此，研究人员开发了靶向FGFR4的CAR-T细胞，如RJ154-HL和3A11，具有不同的靶向FGFR4的scFv。目前，靶向FGFR的CAR-T细胞也仍处于临床前开发阶段。基于抗体的药物Aprutumab是一种全人源抗FGFR2抗体，它识别FGFR2b和FGFR2c亚型共同N末端区域P23、L27和E29周围的表位，并已被证明能诱导这些变体的内化和运输至溶酶体降解。Aprutumab和bemarituzumab在I期临床试验中均显示出良好的安全性和耐受性。目前，bemarituzumab已作为联合疗法进行II期和III期临床试验，而Aprutumab用于开发ADCs和RICs。Aprutumab ixadotin（前身为BAY-1187982）是具有不可裂解连接子的抗FGFR2 ADC，LY3076226是具有可裂解连接子的抗FGFR3 ADC。然而，测试这两种药物的第一阶段试验(nct22368951)由于耐受性差和活性有限而终止。此外，Aprutumab和抗FGFR3抗体vofatamab分别用于FGFR2靶向的RIC（227Th-Aprutumab，BAY 2304058）和FGFR3靶向的RIC，225Ac-vofatamab（FPI-1966）和111In vofatamab（FPI-1967）。BAY 2304058仍处于临床前开发阶段，而FPI-1966（用于放射免疫疗法）和FPI-1967（用于放射成像）目前正在I/II期试验(NCT05363605)中进行测试，用于表达FGFR3的晚期实体瘤患者。可溶性FGFR受体可溶性FGFR受体，如衍生自FGFR1c的细胞外结构域的FP-1039和衍生自FGFR 3c的细胞外区域的Recifecept，是另一类通过充当诱饵受体来捕获FGFR配体的重组蛋白药物。FP-1039已显示对促有丝分裂FGF配体具有高亲和力，并且在FGFR1扩增的肺癌和FGFR2突变的子宫内膜癌的小鼠异种移植模型中具有抗肿瘤作用。FP-1039在一期试验中具有可接受的耐受性。测试FP-1039与各种化疗联合用药的Ib期试验(NCT01868022) 显示同时接受紫杉醇和卡铂治疗的鳞状非小细胞肺癌患者的ORR为47%，同时接受培美曲塞和顺铂治疗的恶性胸膜间皮瘤患者的ORR为39%。小结目前，小分子FGFR抑制剂和FGFR靶向抗体药物已在临床后期试验中进行开发和测试，其中几种小分子FGFR抑制剂已被批准用于FGFR改变的癌症患者。尽管如此，某些不良事件，如FGFR1脱靶抑制引起的高磷血症和获得性耐药性，仍然限制了这些药物的临床益处。选择性第三代抑制剂，如特异性靶向FGFR2或FGFR3的抑制剂，正在临床开发中，这些药物可能避免或显著降低高磷血症的风险，并可能克服突变介导的耐药性。参考文献：1.FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions. Nat Rev Clin Oncol.2024 Feb 29声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

放射疗法