Recalcitrant cancer: SCLC

Lung cancer remains the most prevalent new cancer incidence globally, and SCLC is responsible for about 13% of those new cases [4]. SCLC is highly aggressive, estimated to kill an estimated 250,000 people worldwide every year [16]. SCLC is basically classified into two main groups, namely limited-stage SCLC (LS-SCLC) and extensive-stage SCLC (ES-SCLC). Based on this classification, SCLC treatment differs. For LS-SCLC, standard therapy includes cisplatin/etoposide chemotherapy combined with radiotherapy [17]. A prophylactic cranial irradiation (PCI) is also administered to prevent future metastasis to the brain [17]. Mainly for ES-SCLC, current frontline treatment includes the administration of chemotherapeutic drugs cisplatin and etoposide in combination with immunotherapeutic drugs targeting immune checkpoint inhibitors (programmed death-ligand 1[PD-L1] or cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) [17]. A comparative timeline of the treatment advancement and patients’ survival is depicted in Figure 1. Likewise, Tariq et al. published an updated management of SCLC [18].

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Figure 1. Schematic timeline of SCLC FDA-approved therapies and 5-year patients’ survival in the last four decades [17, 19]. National Comprehensive Cancer Network (NCCN) recommended therapies are presented in unshaded boxes, while full FDA-approved therapies are shaded in green boxes [17]. ES-SCLC: extensive-stage small-cell lung cancer; LS-SCLC: limited-stage small-cell lung cancer; PCI: prophylactic cranial irradiation.

Consequently, although the overall incidence and mortality rate of SCLC are gradually decreasing in the USA, a commensurate increase in SCLC patients’ 5-year survival remains approximately 7%, a little improvement from 6.4% reported between 2002 and 2012 [19, 20]. Of note, recent advances in the understanding of SCLC tumor biology and/or immunity led to the development of immunotherapies with/without chemotherapy. This, combined with better detection techniques and awareness campaigns, might play a part in the modest improvement in ES-SCLC 5-year patient survival stated above. Scientists and other oncology health practitioners rightfully identified the imminent need to develop new therapeutic modalities, such as RNA therapeutics discussed below.

Recalcitrant cancer: PDAC

Globally, PDAC accounts for 90% of total pancreatic cancer and is currently the 4th leading cause of cancer-related deaths [21], while in the USA, it has surpassed breast cancer to become the 3rd leading cause of cancer-related mortality [22]. The treatment strategy for PDAC patients, like most aggressive carcinomas, depends on disease stage or advancement at detection. Treatment options invariably determine the ultimate outcomes in the form of patient survival. Unfortunately, 90 percent of PDAC cases are detected at an advanced disease stage characterized by high disease aggression, poor prognosis, and low survival [21, 22]. In general, PDAC treatment consists of a combination of surgical resection and multi-agent systemic chemotherapy [23]. First-line treatment involves the administration of 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) [22, 23]. Meanwhile, other chemotherapies such as Gemcitabine or a combination of gemcitabine and paclitaxel are administered as a second-line treatment [22, 23]. Only a small fraction of PDAC patients (15–20%) qualify for and benefit from surgical resection [22, 23].

Figure 2 shows the trend of pancreatic cancer, including PDAC new incidence and mortality rate in the last 15 years, while Table 1 summarizes gender specific statistics of pancreatic cancer, which PDAC accounts for approximately 90%, in the USA within the same period. Considering all stages of PDAC, in the USA, overall PDAC 5-year survival still stands at 13% [4, 21–24]. Meanwhile, when PDAC is detected early (stage IA) through adequate surveillance of patients with familial gene susceptibility or abdominal imaging for other ailments, the 5-year survival of patients increases to 20% or higher [25]. Looking back 15-years, all stages PDAC 5-year survival in the year 2010 was 6% [26] compared to 13% in the year 2025 [4] as reported by the American Cancer Society. That is literally a 116% increase in patients’ survival. Despite this remarkable improvement, scientists have identified more strategies that will promote improvement and drive further increase in PDAC patients’ survival, such as intensifying research efforts to understand PDAC at the molecular level with a focus on novel treatment agents preventing the growth, metastasis, and invasion of the disease [21, 27]. Likewise, novel tumor-targeted therapies, including new-generation immunotherapies and RNA therapies, might help [23].

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Figure 2. Trends of pancreatic cancer, including Pancreatic Ductal Adenocarcinoma (PDAC), estimated new cases and deaths in the USA within the last 15 years [5, 28–36].

Clinical development of RNA drugs targeting SCLC and PDAC

The World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) is a unified public database for information about global clinical trials. The ICTRP data is contributed by 20 clinical trials registries around the world. Using a combination of keywords such as “SCLC and RNA drug” and “PDAC and RNA drug” returned no results on the ICTRP search portal. Meanwhile, search for “RNA drug” on the ICTRP portal returned 120 clinical trial results with none specifically investigating RNA-based modality for SCLC or PDAC. Notwithstanding, a phase 1 clinical trial from China with registration number ChiCTR2200056172 was observing and evaluating the safety of RNA tumor vaccine injection alone or in combination with Programmed cell death protein 1 (PD-1) inhibitor for the treatment of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant advanced solid tumors. Since the majority of PDAC cases are KRAS mutation-driven, this trial might consider recruiting PDAC patients. Although this trail was last updated in August, 2024. Similarly, a European phase 1/2a clinical trial (EUCTR2019-004323-20-DE) was evaluating the safety and preliminary efficacy of Claudin 6 (CLDN6) chimeric antigen receptor T-cell therapy (CAR-T) with or without an RNA vaccine (CLDN6 RNA-LPX) in patients with CLDN6-positive relapsed or refractory advanced solid tumors. Although no specific mention of PDAC and SCLC, their inclusion criteria stated that the patient must have a histologically confirmed solid tumor that is metastatic or unresectable. SCLC and PDAC patients might qualify for this clinical trial. This trial was also last updated in July, 2024. ICTRP can be accessed at the web address (https://trialsearch.who.int/Default.aspx). Further pairing of specific RNA forms, such as small interfering RNA (siRNA), long non-coding RNA (lncRNA), circRNA, antisense oligonucleotide (ASO), and microRNAs (miRNAs) with PDAC or SCLC did not return any result.

We further specifically searched Clinicaltrials.gov, the largest clinical trial registry in the world, using the same keywords as explained above: NCT03608631 was discovered. NCT03608631 is a phase I study of mesenchymal stromal cell-derived exosomes with KRASG12D siRNA for metastatic pancreatic cancer patients harboring the KRASG12D mutation. This trial is still recruiting and is expected to be concluded in April, 2027. On the same note, we investigated pipelines of top RNA therapeutics companies and start-ups such as Moderna, BioNTech, Orna Therapeutics, Anylam Therapeutics, and so on. Our research showed that Moderna has the most advanced clinical trials for developing an oncology-based RNA drug. Unfortunately, SCLC and PDAC are not included in those cancers under Moderna’s investigative drug discovery pipeline. Therefore, so far, clinical development efforts of RNA drugs for recalcitrant cancers such as SCLC and PDAC are very limited. This further substantiates the call for improved exploitation of RNA therapeutic platforms in combating debilitating diseases known as SCLC and PDAC.

Our discussion so far has summarily present literatures about the introduction, classification, statistics, clinically approved treatment modalities, and development of prospective RNA drugs for recalcitrant cancers such as SCLC and PDAC. It is obvious that current research efforts towards discovering long-lasting efficacious treatment for SCLC and PDAC can benefit tremendously from exploring RNA therapeutic modalities. On the same note, rare cancers are known to receive even less research attention. Therefore, we will attempt to provide a brief background on rare cancers and summarise current literature about rare cancer diagnosis, statistics, clinical treatment, and the prospect of RNA drug exploitation in developing more effective treatment for certain rare cancers.

Comparative statistics over two decades

A long-term analysis of rare cancer trends highlights both challenges and progress in incidence and survival outcomes. Over the past two decades, advancements in diagnostic techniques, including molecular imaging and NGS, have contributed to earlier detection and improved characterization of rare cancers. Simultaneously, therapeutic innovations such as immunotherapies, targeted therapies, and RNA-based treatments have significantly enhanced survival rates across various cancer types. The incidence and survival trends for rare cancers (Table 2) underscore the gradual improvements in survival outcomes for rare cancers over two decades, driven by advancements in early detection, targeted therapies, and supportive care innovations. However, the modest increases in incidence highlight the ongoing need for research into prevention and environmental or genetic risk factors. The following table, derived from the Global Cancer Observatory and SEER Database, provides a comprehensive comparison of incidence rates and 5-year survival rates from 2003, 2013, and 2023, illustrating these trends [36, 40].

Clinical trial improvement in the last decade

Clinical trials for rare cancers have historically faced challenges, including small patient populations, heterogeneous disease presentations, and limited funding. However, recent innovations have addressed these barriers, leading to significant progress in drug development and patient outcomes. The data presented in this section are derived from analyses of publicly available clinical trial databases, including ClinicalTrials.gov and the WHO’s ICTRP, as well as peer-reviewed publications and industry reports [41–43].

Advances in rare cancer research

Adaptive Trial designs: Clinical trial platforms such as the National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) and the Targeted Agent and Profiling Utilization Registry (TAPUR) allow for the inclusion of rare cancer subtypes by utilizing shared control groups and flexible endpoints. These designs improve efficiency and reduce the burden on small patient populations. A pivotal study by [44] demonstrated that NCI-MATCH successfully matched patients with rare cancer subtypes to targeted therapies based on genetic profiles, leading to improved treatment outcomes. Additionally, the TAPUR trial has shown the efficacy of repurposing FDA-approved drugs for off-label use in rare cancers with specific molecular targets [45, 46].

Biomarker-driven studies: The identification and validation of molecular biomarkers, including RNA-based signatures, have enabled patient stratification, maximizing trial success rates by targeting responsive subgroups. For example, the use of PD-L1 expression as a predictive biomarker in immune checkpoint inhibitor trials has transformed treatment approaches for cancers like Merkel cell carcinoma, a rare skin cancer [47, 48].

Global collaboration: International consortia such as Expert Care for Rare Adult Solid Cancer (EURACAN) and Rare Cancers Europe have pooled resources to conduct larger, more robust trials, thereby addressing challenges associated with limited patient enrollment. This collaborative approach has also improved data sharing and standardization of protocols. A notable success was the EURACAN-led study on sarcomas, which pooled over 500 patients across 20 countries, resulting in the development of standardized treatment guidelines and identification of novel therapeutic targets [49, 50]. Moreover, Rare Cancers Europe has advanced policy changes to increase funding and collaboration opportunities for rare cancer research.

These key advances underscore the importance of leveraging innovative trial designs, biomarkers, and global networks to overcome the inherent challenges of rare cancer research. As the field of RNA therapeutics continues to evolve, integrating these strategies into trial frameworks will be critical for accelerating the development of effective therapies and improving patient outcomes.

Advances in RNA-based therapeutics for rare tumors

The emergence of RNA therapeutics: historical foundations and translational breakthroughs

Ground breaking discovery in RNA biology gained its momentum in 1961 when Jacob and Monod [70] theorized the presence of mRNA. By the 1990s, miRNAs were recognized for their role in post-transcriptional gene silencing [71], followed by the discovery of small nucleolar RNAs (snoRNAs), piwi-interacting RNAs (piRNAs) [72], lncRNAs [73–76], and recently circRNAs [77, 78]. These breakthroughs have certainly redefined the roles of RNA in biology, offering novel perspectives on genetic regulation and diseases.

Building on previous cutting-edge research, RNA-based therapeutics have progressively advanced the landscape of medicine, resolving unmet clinical needs through precise and innovative technologies. Key RNA therapeutic classes discovered over the years include ASOs, RNA aptamers, siRNAs, mRNA vaccines, and lipid-based nanotechnology. ASO technology was first introduced in 1978 when Zamecnik et al. [79] and Stephenson et al. [80] demonstrated its potential to suppress Rous sarcoma virus activity in chicken embryos. After two decades of extensive research in ASO, these efforts led to the FDA approval of Fomivirsen [81], the first RNA-based therapeutics delivered via intravitreal injection, for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients [81].

After the approval of ASO, RNA research and therapeutic efforts intensified towards combating mostly non-oncology diseases. Another notable historical discovery includes RNA aptamer-based drug, Macugen (pegaptanib), for treating age-related macular degeneration (AMD), marking a significant milestone in its clinical application [82]. In 2004, the first siRNA clinical trial, AGN211745 (siRNA-027), was initiated, targeting the VEGF signaling pathway to treat wet neovascular AMD [83]. This provided key evidence for the therapeutic potential of RNA interference (RNAi) using siRNAs as therapeutic tools. Subsequently, the FDA approved the first siRNA-based drug, Patisiran, in 2018 [84]. CRISPR technology also ushered in a powerful therapeutic system, which combined the enzymatic activity of an endonuclease with single guide RNA (sgRNA) to target disease-associated genetic (DNA and RNA) targets in various prokaryotic and eukaryotic biological systems. In 2023, the FDA approved exagamglogene autotemcel (exa-cel), the first CRISPR-based therapy, marking a major milestone in genetic medicine [85].

The most practical application of RNA therapeutic importance was witnessed during the COVID-19 pandemic in 2020. The principle of mRNA vaccines is based on the use of messenger RNA to instruct cells to produce a viral protein, thereby stimulating an immune response. mRNA vaccines deliver the genetic blueprint for the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in LNPs, prompting cells to generate the protein and trigger an immune reaction [86]. This approach enables rapid vaccine development and facilitated the swift development of mRNA vaccines during the COVID-19 pandemic, contributing to the 2020 release of the Pfizer-BioNTech and Moderna COVID-19 vaccines [87].

LNP technology, developed in the early 1970s by scientists Gregoriadis and Ryman [88, 89], is a crucial advancement in RNA therapeutics for efficient RNA delivery. LNPs, nanoscale lipid-based carriers, encapsulate RNA molecules like siRNAs, protecting them from degradation and facilitating targeted delivery to specific tissues [90, 91]. This innovative delivery system has revolutionized RNA-based therapies, making them viable for treating various diseases, including genetic disorders and cancers. LNPs enhance the stability, efficiency, and tissue-specific targeting of RNA molecules, providing a foundation for high-impact clinical applications [92]. The clinical success of LNP-formulated RNA therapeutics is demonstrated by several FDA-approved drugs: Patisiran, which was the first LNP-formulated siRNA drug to treat hereditary transthyretin-mediated amyloidosis (hATTR), a rare genetic disorder [84]. Givosiran targets aminolevulinic acid synthase 1 (ALAS1) for acute hepatic porphyria (AHP), another rare metabolic disorder [93]. In 2023, Nedosiran (Rivfloza) was approved, targeting lactate dehydrogenase A (LDHA) for primary hyperoxaluria type 1 (PH1) [94]. These approvals underscore the transformative potential of LNP-based RNA therapeutics in treating genetic and metabolic diseases, highlighting LNP technology as a key enabler in advancing RNA-based treatments.

Validated RNA therapeutic platforms in non-malignant diseases

RNA-based therapies are an emerging and rapidly advancing field, particularly in the treatment of rare diseases. Although RNA-based approaches show growing promise for targeting difficult-to-treat cancers, their application in oncology remains largely limited to ongoing clinical trials. While the FDA’s approval of certain RNA therapies highlights their potential, their full impact, safety concerns, and long-term effectiveness are yet to be fully established in recalcitrant cancers. Here are some notable examples of successful RNA-based treatments in rare diseases. A full list is presented in Table 3 below.

Why RNA therapeutics are still limited in rare cancers

RNA-based drugs (siRNA, miRNA, lncRNA, and mRNA vaccines) have made major strides, but most advances and trials are concentrated in common solid tumors (melanoma, NSCLC, prostate, pancreatic) and hematologic malignancies, not rare cancers [102–105]. Several factors explain this gap:

• 1.

  Biology and target discovery: Many rare cancers lack deep multi‑omic characterization, so the disease‑specific RNA targets (oncogenic miRNAs/lncRNAs, neoantigens for mRNA vaccines) are less well defined than in common tumors. lncRNA targeting in particular depends on cell‑type restricted expression maps that are incomplete for rare entities [106–108].

• 2.

  Delivery and pharmacology challenges: Efficient, safe delivery of RNA into tumor tissue is still a major bottleneck. Current LNP and other formulations work best for liver and some well‑vascularized tumors, but struggle with deep, heterogeneous solid tumors, which is especially problematic when only very small, dispersed patient populations are available to optimize dosing and delivery. Suboptimal delivery and off‑target effects have already caused termination of several oncology RNA trials [108–113].

• 3.

  Safety, off‑target effects, and incomplete RNA biology: miRNA and lncRNA therapeutics can act on many transcripts at once, making specificity and toxicity difficult to control, which may lead to early‑phase failures and a cautious regulatory stance. For many ncRNAs (ncRNAs), functional roles in specific rare tumor contexts remain poorly understood, limiting rational drug design [114].

• 4.

  Small, fragmented patient populations and trial design: Rare cancers make it hard to run adequately powered, stratified RNA trials and to embed complex pharmacodynamic, immune, and biomarker endpoints that RNA agents require [111]. Reviews of ncRNA clinical trials emphasize that, even in common cancers, most work is still early phase with heterogeneous designs; scaling that to many rare indications is a major logistical and financial barrier [104, 106].

• 5.

  Economic and regulatory constraints: Manufacturing scale‑up, cold‑chain logistics, and evolving regulatory pathways for novel modalities (siRNA, circRNA, engineered lncRNAs) add cost and uncertainty, which companies preferentially absorb in large indications rather than rare tumors. Approved RNA drugs have largely targeted rare genetic diseases where systemic delivery and clear single‑gene targets are more tractable than in heterogeneous rare cancers 618. Overall, the field is still solving platform‑level issues, such as delivery, specificity, safety, and manufacturing, which are being addressed first in more common cancers before being extended to small, rare‑cancer populations.

Oncogenic RNA therapeutic prospects in recalcitrant and rare cancers now and in the future

Recent progress has positioned RNA therapeutics at the core of a new precision oncology landscape. While earlier RNA medicines primarily targeted inherited or metabolic disorders, current developments are moving into solid and hematologic malignancies, a group of diseases characterized by high fatality and therapeutic recalcitrance. Following the policy impetus of the Recalcitrant Cancer Research Act of 2012, multiple RNA oncology programs have entered the clinic [1, 2]. RNA‑based therapeutics indeed represent a promising strategy for treating rare cancers, particularly those that are resistant to conventional modalities such as chemotherapy, radiotherapy, monoclonal antibodies, and immunotherapy. By modulating RNA transcripts, these therapies enable the regulation of oncogene expression, the restoration of tumor suppressor gene function, and the correction of genetic mutations, offering personalized treatment options tailored to the specific genetic alterations driving individual cancers [111]. Furthermore, their non-integrative and degradable nature ensures safety, positioning RNA therapeutics as an innovative alternative to traditional and DNA-based treatments in cancer care [111]. Current research has shown that RNA-based strategies, such as RNAi, RNA-based CAR-T cell therapies, and mRNA vaccines, are being explored for their ability to target key pathways involved in cancer progression. Early-phase clinical trials have demonstrated promising results, particularly in hematologic and solid tumors [115].

To date, over 120 RNA-based cancer trials are active or may have been completed according to ClinicalTrials.gov and WHO ICTRP searches [68]. Among these, Moderna’s mRNA-4157/V940 (NCT03897881) and BioNTech’s BNT122 (autogene cevumeran) (NCT05142189) represent personalized neoantigen vaccines in melanoma, non-SCLC, and pancreatic carcinoma. The study outcome of phase 2 results demonstrated a 44% reduction in recurrence risk when combined with pembrolizumab compared to checkpoint blockade alone [116–119]. These vaccines deliver synthetic mRNA encoding TAAs to dendritic cells (DCs), which process and present the antigens on major histocompatibility complex (MHC) class I molecules, activating CD8+ T cells to target and destroy cancer cells. The vaccines offer several advantages, such as the ability to present multiple epitopes, bypass HLA type limitations, and enable rapid, scalable production without the need for nuclear localization. However, challenges remain, including the identification of tumor-specific neoantigens, optimizing delivery methods, and managing immune overactivation [120]. Recent work has also showcased a leading example of an LNP‑delivered, pan‑KRAS siRNA formulation encapsulated in microparticles, designed to target multiple KRAS mutations beyond G12C. In this context, the SIL‑204 siRNA exerts its antitumor activity in locally advanced pancreatic cancer [121, 122]. These data support the biological feasibility of KRAS-targeted siRNA strategies in pancreatic cancer and provide a translational framework for the future development of clinically viable KRAS-directed RNA therapeutics.

RNA-based CAR-T cell therapies offer significant benefits over traditional viral vector approaches, as they enable transient CAR expression and reduce the risk of severe adverse effects associated with permanent genetic modifications [123]. Electroporation is currently the most common method for delivering CAR-encoding mRNA into T cells, while innovative delivery systems such as LNPs, exosomes, polymer-based particles, and peptide transduction domains are actively being explored [124, 125]. Additionally, gene editing technologies like CRISPR/Cas9 and Cas13 offer precise, durable, and customizable treatments, presenting advantages over traditional therapies. Unlike siRNA-based therapies, which provide only transient suppression of gene expression, CRISPR directly edits DNA, ensuring permanent correction of targeted mutations [126]. The CRISPR-Cas9 system, along with newly discovered Cas12 and Cas13, holds significant potential for both gene editing and RNA-targeted therapies and diagnostics [127]. Concisely, further research and clinical trials are necessary to fully evaluate the safety, efficacy, and long-term outcomes of CRISPR-based therapies.

RNA-based therapies are currently in pre-clinical or early clinical development, and their potential to target the genetic drivers of challenging cancers positions them as a promising avenue for future FDA-approved treatments. Advances in safety, nanoparticle delivery, and next-generation chemistries are also expected to further enhance their therapeutic impact. Looking ahead, RNA therapeutics are anticipated to revolutionize personalized medicine by enabling customized treatments tailored to individual patients’ genetic mutations or resistance mechanisms, thereby improving outcomes and reshaping the landscape of recalcitrant cancer therapy. Finally, Table 4 presents an updated summary of all FDA-approved RNA therapeutics, their indication, molecular targets, and delivery modality.