Precision medicine: Recent advances in targeted therapies for solid tumour treatment

 

Over 90% of newly diagnosed cancers are solid tumours, which includes those with the highest mortality rates such as breast, lung, colorectal and prostate cancer [1,2]. Surgical resection and chemotherapy, once the backbone of solid tumour management, are increasingly limited by poor target specificity, chemotherapy resistance and tumour recurrence [3,4]. These traditional treatment strategies have steadily been complemented and in some cases replaced by therapies designed to target specific biological vulnerabilities of cancer cells. Today, such targeted therapies represent one of the most rapidly evolving areas in oncology, fuelled by advances in drug engineering and artificial intelligence (AI), with the aim of improving the toxicity profiles of available treatments and reducing rates of relapse.

Antibody-based therapies: Exploiting nature’s own targeting system

Antibody-based therapies are designed to improve the specificity of immunotherapy drugs and include monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs) and bispecific antibodies (BsAbs). These therapies act by targeting specific markers found on cancer cells rather than activating the entire immune system, allowing for the targeting of specific cancer cells rather than healthy tissue.

The engineered mAb is designed to recognise a specific marker on the surface of a cancer cell and attach to it, blocking the signals that cause the cancer to grow [5,6]. Rituximab, approved by the US Food and Drug Administration in 1997 for the treatment of follicular lymphoma, was the first therapeutic mAb approved for cancer treatment and was the top-selling oncology drug for nearly a decade [7]. Rituximab works by binding to a protein found on developing B cells, called cluster of differentiation 20 (CD20), and is used to treat B-cell malignancies such as non-Hodgkin lymphoma [7]. It has improved patient outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukaemia, leading to the development of mAb therapies for solid tumour treatment [7]. One such treatment is trastuzumab, a mAb that targets human epidermal growth factor receptor 2 (HER2), which is a protein found at very high levels in approximately 20%–30% of breast cancers. This drug has improved outcomes for people with HER2‑positive breast cancer, although some cancers may still become resistant and spread, which remains a major challenge [5].

With advancements in technology, ADCs were developed to overcome the challenges in standard antibody therapies. ADCs combine the accuracy of antibodies, which can seek out cancer cells, with the efficacy of chemotherapy drugs. A mAb is joined to a drug by a chemical linker, enabling the drug to be delivered directly into cancer cells while reducing side effects in healthy tissue (Figure 1). Compared with conventional chemotherapy, ADCs demonstrate enhanced precision, effectiveness and safety [4]. One major study, the KATHERINE trial, followed 1,486 patients who received either trastuzumab emtansine (an ADC) or standard trastuzumab after surgery. After 3 years, 88.3% of patients treated with the ADC were free of invasive cancer, compared with 77.0% of those who received the antibody alone, showing a meaningful improvement in patient outcomes [8].

Even within the ADC class, rapid advancements in mAbs, linkers, payloads and linker technologies allow for continual development [4]. One of the more recent developments is trastuzumab deruxtecan, an ADC that targets the HER2 protein. A large international Phase III study, DESTINYBreast05, compared trastuzumab deruxtecan with the current standard ADC treatment, trastuzumab emtansine, in patients with early-stage HER2-positive breast cancer. Patients receiving trastuzumab deruxtecan were significantly more likely to remain free of invasive cancer than those on trastuzumab emtansine, highlighting how ongoing research in this area is leading to improved outcomes for patients [9].

Alongside ADCs, BsAbs are gaining momentum. These engineered molecules can bind two targets simultaneously; for example, bringing T cells into direct contact with tumour cells, blocking parallel signalling pathways to overcome therapy resistance, or binding two separate sites on the same protein to enhance binding strength [10]. Zanidatamab is a BsAb engineered to bind two distinct sites on the HER2 protein, triggering immune-mediated cytotoxicity and strongly blocking HER2 signalling that drives cancer growth [11]. In the Phase III HERIZON-GEA-01 trial, the progression-free survival of zanidatamab was 53% longer in both zanidatamab arms compared with the trastuzumab arm in patients with HER2-positive advanced or metastatic gastric and oesophageal adenocarcinoma, showing the promising potential of treatment with BsAbs instead of standard mAB therapy [12].

Figure 1. Mechanism of action of antibody–drug conjugates (ADC) for the targeted treatment of solid tumours.

The antibody region of the ADC binds to its target antigen on the cancer cell, usually one which is upregulated in cancer, causing the antigen–ADC complex to be internalised by the cell. The ADC is broken down, releasing the therapeutic payload into the tumour cell, where the drug can exert effects on its target.

Cellular therapies: Immunotherapy meets genetic engineering

Engineered cell therapies are designed to strengthen or reprogramme a patient’s own immune system to overcome cancer’s immune evasion strategies and attack the tumour more effectively [3]. One of the most well-known approaches in this field uses chimeric antigen receptor T-cell (CAR-T) therapy, which has been successful in treating certain blood cancers, therefore driving interest in developing similar strategies for solid tumours [13]. For more information on CAR-T therapy, please read here.

More recently, researchers have developed T-cell receptor (TCR)-engineered T cells (TCR-Ts) that recognise neoantigens, which are mutation-derived protein fragments found across many tumour types [14]. As these neoantigens arise from changes inside the cancer cell, TCR-Ts can detect intracellular protein changes, offering an advantage over antibody-based or other cell therapies that only target surface markers [3,14]. A recent Phase I clinical trial tested a novel TCR-T therapy, IMA203CD8, that targets the intracellular protein PRAME, which is expressed in over 50 types of cancer [15]. IMA203CD8 demonstrated a manageable safety profile and encouraging activity in 44 patients with PRAME-positive solid tumours with limited treatment options, and trials of this drug are ongoing [15].

AI: Converting computer power into clinical impact

Advances in AI technology have transformed the research landscape in oncology, rapidly reshaping how solid tumours are detected, understood and treated [16]. To aid development of new drugs for solid tumours, AI is able to analyse extremely large and complex data sets. For instance, The Cancer Genome Atlas, which contains detailed genetic information on over 11,000 human tumours from 33 different cancer types, has been analysed by AI systems to identify patterns in molecular profiles across cancers, predict patient outcomes and highlight potential drug targets [17].

AI is also used to power the modelling of new drugs themselves through advanced chemistry simulations. For example, ISM3412, a drug designed using Insilico Medicine’s AI-powered chemistry platform, Chemistry42, was nominated as a preclinical candidate compound in May 2022 [18]. The drug targets cancers with an MTAP deletion, a common genetic alteration found in multiple solid tumours, which leaves the tumour vulnerable to treatment [19]. ISM3412 exploits this vulnerability and selectively kills MTAP-deficient cancer cells while sparing healthy cells. In April 2025, ISM3412 entered its first in-human Phase I trial in patients with locally advanced / metastatic solid tumours [19].

Looking ahead

The field of targeted therapies for solid tumours is advancing at a remarkable speed. From next‑generation ADCs and cell-based therapies to AI techniques, the therapeutic toolbox is continually expanding. However, many other therapeutic strategies are under research and development, including small-molecule inhibitors, kinase inhibitors, DNA-damage repair therapies, epigenetic therapies, vaccines and radiopharmaceuticals, all of which offer promising opportunities for cancer treatment [20]. Coupled with advances in novel biomarker identification and tumour imaging, these developments aim to redefine how we understand and treat cancer at its most fundamental biological levels and improve patient outcomes.

The information in this article is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. All content is for general information purposes only. Always seek the guidance of your doctor or other qualified healthcare professional with any questions you may have regarding your health or medical condition.

 

References

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Author: Megan Stoker Ι Medical Writer Ι Porterhouse Medical