針對(duì)男性第二高發(fā)癌癥，這些療法正在為患者帶來(lái)新的曙光 | Bilingual

編者按：每年9月是前列腺癌宣傳月。前列腺癌是全球男性健康的重大威脅，根據(jù)2024年發(fā)表的全球癌癥統(tǒng)計(jì)數(shù)據(jù)，前列腺癌是男性中第二高發(fā)的癌癥類型，僅在2022年，全球就有超過(guò)146萬(wàn)人確診，占所有癌癥新病例的7.3%。雖然早期篩查、手術(shù)和激素阻斷療法的進(jìn)步顯著提高了早期患者的治愈率，但耐藥與復(fù)發(fā)問(wèn)題依舊是晚期患者面臨的挑戰(zhàn)，在去勢(shì)抵抗性前列腺癌（CRPC）中尤為突出。針對(duì)這一難題，基于多種作用機(jī)制的創(chuàng)新療法已經(jīng)進(jìn)入臨床開發(fā)。長(zhǎng)期以來(lái)，藥明康德通過(guò)“一體化、端到端”的CRDMO模式，持續(xù)支持不同類型前列腺癌創(chuàng)新療法的研發(fā)。本文將聚焦于克服前列腺癌耐藥性的前沿策略，并展示藥明康德在賦能新藥開發(fā)中的作用。

前列腺癌是一種依賴雄激素（如睪酮）驅(qū)動(dòng)增殖的惡性腫瘤，早期往往無(wú)明顯癥狀，確診時(shí)常已進(jìn)入局部晚期或轉(zhuǎn)移階段。20世紀(jì)中葉以前，診斷主要依賴癥狀及直腸指檢，早期發(fā)現(xiàn)率低，治療效果有限。直到20世紀(jì)80至90年代，前列腺特異性抗原（PSA）檢測(cè)的普及大幅提升了早期診斷率和治療機(jī)會(huì)，也顯著降低了患者的死亡率。

在治療方面，自20世紀(jì)40年代Charles Huggins博士與Clarence Hodges博士首次驗(yàn)證睪丸切除術(shù)或雌激素對(duì)轉(zhuǎn)移性前列腺癌的療效以來(lái)，雄激素剝奪療法（ADT）便成為標(biāo)準(zhǔn)的系統(tǒng)治療之一。Huggins博士也因在前列腺癌激素療法上的貢獻(xiàn)，于1966年獲得諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng)。隨著醫(yī)學(xué)發(fā)展，更溫和且可逆的治療方式陸續(xù)出現(xiàn)，包括促性腺激素釋放激素（GnRH）激動(dòng)劑、拮抗劑及抗雄激素藥物，成為臨床治療的重要手段。這些療法能夠有效降低體內(nèi)雄激素水平，從而抑制腫瘤進(jìn)展。

然而，盡管ADT在短期內(nèi)能夠控制病情，大多數(shù)患者最終仍會(huì)發(fā)展為CRPC。一旦癌細(xì)胞擺脫對(duì)雄激素的依賴，預(yù)后便會(huì)急劇惡化，使CRPC成為臨床上極具挑戰(zhàn)性的疾病階段。

聚焦“合成致死”機(jī)制

在治療前列腺癌的小分子研發(fā)管線中，研發(fā)人員嘗試的重要方向之一，是通過(guò)靶向AR以外的信號(hào)通路解決前列腺癌的耐藥性。其中，基于“合成致死”機(jī)制開發(fā)的多款創(chuàng)新療法已經(jīng)獲得監(jiān)管機(jī)構(gòu)批準(zhǔn)上市，例如，PARP抑制劑Rubraca（rucaparib）與Lynparza（olaparib）已經(jīng)獲批用于治療攜帶

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新一代放療：放射性配體藥物

體外放射治療（EBRT）是治療早期前列腺癌的重要手段之一，但對(duì)于全身轉(zhuǎn)移的mCRPC患者，EBRT僅能緩解部分病灶，且存在損傷健康組織的風(fēng)險(xiǎn)。2013年，美國(guó)FDA批準(zhǔn)了放射性療法Xofigo（Ra 223 dichloride），用于治療出現(xiàn)骨轉(zhuǎn)移的前列腺癌患者。其特性可模擬鈣元素，被快速增長(zhǎng)的骨轉(zhuǎn)移瘤吸收，從而實(shí)現(xiàn)對(duì)骨轉(zhuǎn)移瘤的靶向殺傷。為了進(jìn)一步提高放射性療法的精準(zhǔn)性，研究人員開發(fā)了放射性配體藥物，通過(guò)將同位素與特異性配體結(jié)合，實(shí)現(xiàn)將放射性藥物精準(zhǔn)遞送至腫瘤細(xì)胞，從而減少對(duì)正常組織的損害。

基于這一理念開發(fā)的Pluvicto（lutetium Lu 177 vipivotide tetraxetan）已獲FDA批準(zhǔn)，用于治療前列腺特異性膜蛋白（PSMA）陽(yáng)性的經(jīng)治mCRPC患者。當(dāng)前，全球已有40余款放射性配體藥物正在臨床階段探索治療前列腺癌的潛力，靶點(diǎn)主要為PSMA，還包括SSTR2、GRPR、DLL3、NTSR1、KLK2等。靶向配體形式涵蓋小分子、抗體與多肽，所用放射性同位素包括Lu 177、Ac 225、Ga 68、In 111等。

圖片來(lái)源：123RF

雖然放射性配體藥物在早期腫瘤成像和治療方面均展現(xiàn)巨大潛力，但其藥物結(jié)構(gòu)復(fù)雜，通常由靶向配體、連接子、螯合劑和放射性同位素組成，其生產(chǎn)過(guò)程需要多學(xué)科的專業(yè)技術(shù)支持。藥明康德綜合性的放射性藥物發(fā)現(xiàn)平臺(tái)整合了多肽發(fā)現(xiàn)和放射性藥物開發(fā)能力，提供包括多肽合成、螯合劑合成、放射性標(biāo)記、成像、藥理學(xué)研究和監(jiān)管申報(bào)支持等完善的服務(wù)。一體化平臺(tái)讓多個(gè)團(tuán)隊(duì)并行攻堅(jiān)、高度協(xié)作，幫助合作伙伴快速推動(dòng)項(xiàng)目進(jìn)展，節(jié)省寶貴的開發(fā)時(shí)間。

靶向蛋白降解與誘導(dǎo)接近藥物

為了應(yīng)對(duì)ADT耐藥性，研究者開發(fā)了多種靶向AR信號(hào)通路的創(chuàng)新策略。其中，靶向蛋白降解藥物（TPD）為克服傳統(tǒng)AR拮抗劑耐藥性帶來(lái)新希望。它們通過(guò)直接降解AR蛋白，可更深度、持久地抑制AR信號(hào)通路。例如，Arvinas公司開發(fā)的第二代AR靶向蛋白降解嵌合體（PROTAC?）ARV-766在早期臨床試驗(yàn)中表現(xiàn)出能夠選擇性降解野生型和帶有臨床耐藥相關(guān)突變的AR的能力。諾華（Novartis）已與Arvinas達(dá)成超10億美元獨(dú)家許可協(xié)議，獲得該療法的全球開發(fā)和商業(yè)化權(quán)益。公開資料顯示，目前已有10多款TPD療法進(jìn)入臨床階段，用于治療前列腺癌。

TPD之外，基于誘導(dǎo)接近（induced proximity）機(jī)制開發(fā)的調(diào)節(jié)誘導(dǎo)接近靶向嵌合體（RIPTAC）藥物HLD-0915也已經(jīng)進(jìn)入臨床。HLD-0915通過(guò)將AR與一個(gè)與轉(zhuǎn)錄調(diào)控相關(guān)的關(guān)鍵蛋白“綁”在一起，讓細(xì)胞啟動(dòng)凋亡程序并死亡。在前列腺癌小鼠模型中，RIPTAC的表現(xiàn)已經(jīng)優(yōu)于多款獲批的AR拮抗劑和雄激素合成抑制劑。

在助力TPD療法從創(chuàng)新概念走向臨床驗(yàn)證的過(guò)程中，藥明康德致力于支持全球客戶加速研發(fā)進(jìn)程，憑借CRDMO平臺(tái)能夠“端到端”助力TPD分子從發(fā)現(xiàn)、到開發(fā)，再到生產(chǎn)交付的全過(guò)程。藥明康德已經(jīng)助力70多種TPD分子進(jìn)入臨床前候選藥物（PCC）階段，10多種已進(jìn)入后期開發(fā)階段。

在上述介紹的療法類型之外，個(gè)體化癌癥疫苗以及雙特異性抗體等免疫療法也在前列腺癌臨床試驗(yàn)中展現(xiàn)積極信號(hào)。在這個(gè)前列腺癌宣傳月，我們期待更多創(chuàng)新診療手段取得突破，為患者延長(zhǎng)生命、提升治愈希望。未來(lái)，藥明康德將繼續(xù)依托其“一體化、端到端”的CRDMO模式，攜手全球合作伙伴，共同實(shí)現(xiàn)“讓天下沒(méi)有難做的藥，難治的病”的愿景。

Shedding Light on the Second Most Common Cancer in Men: Hundreds of Investigational Drugs Are Bringing New Hope

September is Prostate Cancer Awareness Month. Prostate cancer remains a major threat to men’s health worldwide. According to the global cancer statistics published in 2024, it is the second most common cancer among men, with more than 1.46 million new cases diagnosed in 2022 alone—accounting for 7.3% of all new cancer cases. Advances in early screening, surgery, and hormone-blocking therapies have significantly improved cure rates for patients diagnosed at an early stage. Yet for those with advanced disease, resistance and relapse remain formidable challenges, particularly in castration-resistant prostate cancer (CRPC). To address these unmet needs, innovative therapies based on diverse mechanisms of action are progressing through clinical development. WuXi AppTec has long supported the development of such therapies through its fully integrated, end-to-end CRDMO services. This article explores the forefront of treatment strategies aimed at overcoming resistance in prostate cancer and highlights WuXi AppTec’s role in enabling new drug innovation.

Prostate cancer is an androgen-dependent malignancy, typically driven by hormones such as testosterone. In its early stages, it often presents without obvious symptoms, and many cases are diagnosed only once the disease has progressed to locally advanced or metastatic stages. Prior to the mid-20th century, diagnosis relied largely on symptoms and digital rectal examination, leading to low detection rates and poor treatment outcomes. The introduction and widespread adoption of prostate-specific antigen (PSA) testing during the 1980s and 1990s marked a turning point, dramatically increasing early detection and treatment opportunities while significantly reducing mortality.

On the therapeutic front, androgen deprivation therapy (ADT) has been the cornerstone of systemic treatment since the 1940s, when Dr. Charles Huggins and Dr. Clarence Hodges first demonstrated that orchiectomy or estrogen could effectively treat metastatic prostate cancer. For his groundbreaking contributions, Dr. Huggins was awarded the Nobel Prize in Physiology or Medicine in 1966. As medical science advanced, less invasive and reversible approaches—including gonadotropin-releasing hormone (GnRH) agonists, antagonists, and antiandrogens—were introduced, offering more options to suppress androgen production and inhibit tumor growth.

Despite these advances, most patients eventually progress to CRPC. Once cancer cells escape androgen dependence, prognosis worsens dramatically, making CRPC one of the most difficult stages of the disease to manage. This urgent clinical challenge has spurred the development of next-generation therapeutic strategies.

Harnessing the Power of Synthetic Lethality

Beyond AR signaling, researchers are exploring alternative pathways to overcome resistance. One of the most successful approaches has been the use of synthetic lethality. Several therapies developed on this principle have already received regulatory approval. For example, the PARP inhibitors Rubraca (rucaparib) and Lynparza (olaparib) have been approved for patients with

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The pipeline remains rich, with around 40 investigational drugs under development targeting synthetic lethality mechanisms, including PARP, EZH2, ATR, PLK1, POLQ, USP1, and PRMT5.

Emerging synthetic lethality targets are also gaining momentum. PRMT5 inhibitors have shown the ability to selectively kill MTAP-deleted tumor cells, while WRN inhibitors are being studied in tumors with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

Next-Generation Radiotherapy: Radioligand Therapies

External beam radiation therapy (EBRT) has long been a mainstay for early-stage prostate cancer, but for patients with metastatic CRPC, EBRT is limited to treating only a few lesions and carries the risk of collateral damage to healthy tissue. In 2013, the U.S. FDA approved the radiopharmaceutical Xofigo (Ra 223 dichloride) for the treatment of prostate cancer patients with bone metastases. The drug mimics calcium, allowing it to be absorbed by rapidly growing bone metastases and exerting a targeted killing effect. In addition, radioligand therapies (RLTs) are emerging as a more precise alternative. By linking isotopes to tumor-targeting ligands, RLTs deliver radiation directly to cancer cells while sparing normal tissue.

Pluvicto (lutetium Lu 177 vipivotide tetraxetan) is a leading example of this approach. Approved by the FDA for PSMA-positive, previously treated mCRPC patients, Pluvicto has demonstrated meaningful clinical benefit. Globally, more than 40 radioligand therapies are in clinical development for prostate cancer, most targeting PSMA but also receptors such as SSTR2, GRPR, DLL3, NTSR1, and KLK2. Ligands range from small molecules to antibodies and peptides, while isotopes include Lu 177, Ac 225, Ga 68, and In 111.

The complexity of RLTs, which typically consist of a ligand, linker, chelator, and radioactive isotope, requires highly specialized, multidisciplinary expertise. WuXi AppTec’s integrated radiopharmaceutical discovery platform combines peptide discovery with radiopharmaceutical development, offering services from peptide and chelator synthesis to radiolabeling, imaging, pharmacology, and regulatory submission support. This one-stop approach allows multiple teams to collaborate in parallel, accelerating timelines and conserving valuable development resources.

Targeted Protein Degradation and Induced Proximity Therapies

To combat ADT resistance, researchers are exploring new therapeutic strategies to target the AR signaling pathway. Among the most promising is targeted protein degradation (TPD), which offers a way to overcome resistance to conventional AR antagonists. By directly degrading AR proteins, TPD therapies can achieve deeper and more durable inhibition of AR signaling. A leading example is an AR-targeting PROTAC? ARV-766, which in early clinical trials has demonstrated the ability to selectively degrade both wild-type AR and resistant AR mutants. Public data indicate that more than 10 TPD therapies are currently in clinical development for prostate cancer.

Another innovative approach is induced proximity–based therapies. HLD-0915, a regulated induced proximity targeting chimera (RIPTAC) molecule now in clinical trials for metastatic CRPC, forces AR to interact with a key transcriptional regulator, triggering apoptosis and tumor cell death. In preclinical mouse models, RIPTACs have outperformed several approved AR antagonists and androgen synthesis inhibitors.

WuXi AppTec is actively enabling the transition of TPD therapies from concept to clinic. Through its CRDMO platform, the company provides end-to-end support—from discovery and development through to manufacturing—helping accelerate progress. To date, WuXi AppTec has supported the advancement of more than 70 TPD molecules into preclinical candidate (PCC) stage, with over 10 advancing to late-stage development.

Looking Ahead

In addition to these therapeutic strategies, personalized cancer vaccines and novel immunotherapies such as bispecific antibodies are also showing promise in prostate cancer clinical trials. During this Prostate Cancer Awareness Month, we look forward to continued breakthroughs that extend survival and improve the chance of cure for patients. Looking to the future, WuXi AppTec will continue to leverage its fully integrated, end-to-end CRDMO model to accelerate innovation with global partners, advancing toward the shared vision that “Every drug can be made and every disease can be treated.”

參考資料：

[1] State of the art — biomarkers in advanced prostate cancer. Retrieved August 20, 2025, from https://www.nature.com/articles/s41585-025-01080-0

[2] Denmeade & Isaacs (2002). A history of prostate cancer treatment. Nat Rev Cancer., doi: 10.1038/nrc801

[3] Lehtonen & Kellokumpu-Lehtinen (2023). The past and present of prostate cancer and its treatment and diagnostics: A historical review. SAGE Open Med., doi: 10.1177/20503121231216837.

[4] U.S. FDA Approves AKEEGA? (Niraparib and Abiraterone Acetate), the First-And-Only Dual Action Tablet for the Treatment of Patients with BRCA-Positive Metastatic Castration-Resistant Prostate Cancer. Retrieved August 21, 2025, from https://www.jnj.com/media-center/press-releases/u-s-fda-approves-akeega-niraparib-and-abiraterone-acetate-the-first-and-only-dual-action-tablet-for-the-treatment-of-patients-with-brca-positive-metastatic-castration-resistant-prostate-cancer

[5] Bray et al., (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, https://doi.org/10.3322/caac.21834

[6] Zhang et al., (2025). A review of the efficacy of prostate cancer therapies against castration-resistant prostate cancer. Drug Discovery Today, https://doi.org/10.1016/j.drudis.2025.104384

免責(zé)聲明：本文僅作信息交流之目的，文中觀點(diǎn)不代表藥明康德立場(chǎng)，亦不代表藥明康德支持或反對(duì)文中觀點(diǎn)。本文也不是治療方案推薦。如需獲得治療方案指導(dǎo)，請(qǐng)前往正規(guī)醫(yī)院就診。

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