RARE DISEASE
Rare pancreatic disease
Rare pancreatic disease
Rare pancreatic disease
Drug discovery
1
drug
With orphan designation
Overview
Rare pancreatic cancers encompass distinct histologic subtypes such as acinar cell, adenosquamous, colloid, medullary, and signet ring cell carcinomas, representing <15% of pancreatic malignancies [1][15]. These tumors exhibit non-overlapping molecular profiles and clinical behaviors compared to pancreatic ductal adenocarcinoma (PDAC), with some requiring tailored therapeutic approaches due to differential aggressiveness, drug sensitivity, or genetic drivers [1][15]. Diagnosis relies on histopathology and molecular testing to guide management.
Population
Burden
Aggressive clinical courses: >60% present with metastases, contributing to 5-year survival <10% for most subtypes [1][15]
Significant healthcare costs: Late diagnosis and complex treatments account for elevated economic burden [9][14]
Projected 2-fold increase in pancreatic cancer mortality by 2060, with rare subtypes under-represented in epidemiological data [4][12]
Categories: rare gastroenterological diseases
Research Papers
2,306 drug discovery papers about Rare pancreatic disease, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,306 drug discovery papers about Rare pancreatic disease, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-16 | [177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial.
In the phase 3 NETTER-2 study, first-line [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) significantly improved progression-free survival in patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Median progression-free survival was 22·8 months (95% CI 19·4-not estimable [NE]) with 177Lu-DOTATATE vs 8·5 months (7·7-13·8) in the control arm. Here, we report subgroup analyses, including preplanned assessments of efficacy by NET grade (G) and site of origin; further post-hoc analyses are reported in the main text. In this open-label, parallel-group study, patients from nine countries were randomised 2:1 to receive four cycles of 177Lu-DOTATATE plus octreotide long-acting repeatable (LAR) 30 mg every 8 weeks then octreotide LAR 30 mg every 4 weeks, or high-dose octreotide LAR 60 mg every 4 weeks. The primary endpoint (progression-free survival) was previously reported. Tumours were assessed at baseline, week 16, week 24, then every 12 weeks until disease progression or death. Preplanned subgroup analyses used blinded independent centrally reviewed data. The study is registered with ClinicalTrials.gov, NCT03972488, and is completed. Between Jan 22, 2020, and Oct 13, 2022, 261 patients were screened; 35 were excluded due to screen failure, and 226 were randomised. 177Lu-DOTATATE (n = 151) reduced risk of disease progression/death vs control (n = 75) regardless of NET grade/origin (hazard ratio [95% CI]: G2 NET 0·31 [0·18-0·53]; G3 NET 0·27 [0·14-0·49]; pancreatic NET 0·34 [0·20-0·56]; gastrointestinal NET 0·23 [0·12-0·46]). Median progression-free survival in months (95% CI) with 177Lu-DOTATATE was: G2 NET 29·0 (21·8-NE); G3 NET 22·2 (13·9-27·8); pancreatic NET 19·4 (16·6-24·9); gastrointestinal NET NE (22·6-NE). 177Lu-DOTATATE improved objective response rate vs control regardless of NET grade/origin. These findings support the use of first-line 177Lu-DOTATATE for patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive GEP-NETs, and for whom chemotherapy is not considered the most appropriate treatment option, regardless of NET grade (2/3) or origin (pancreas/gastrointestinal). Advanced Accelerator Applications, a Novartis Company.
2026-08-14 | Clinical, genomic, and spatial transcriptomic features of pancreatic adenosquamous carcinoma support subtype-specific therapeutic strategies.
Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to conventional pancreatic ductal adenocarcinoma (PDAC). This study aimed to characterize the clinical outcomes, genomic landscape, and spatial transcriptomic architecture of ASQ. We retrospectively evaluated clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (n=178). Genomic landscapes of ASQ (n=244) versus PDAC (n=29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n=11 from 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). ASQ patients had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (MSI-high, PD-L1+, TMB ³10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, while distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche. Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.
2026-08-13 | Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).
Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in ~ 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates-the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)-and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.
2026-08-07 | SMARCB1 (INI1)-deficient Rhabdoid Pancreatic Carcinoma: A Rare Subtype of Pancreatic Cancer
Rhabdoid pancreatic carcinoma (RPC) is a rare and highly aggressive subtype of undifferentiated pancreatic carcinoma characterized by rhabdoid morphology and frequent loss of SWItch/sucrose non-fermentable chromatin-remodeling complex-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), integrase interactor 1 (INI1) expression.Due to its rarity, its clinicopathological characteristics and optimal management remain poorly defined.A 56-year-old woman with an Eastern Cooperative Oncology Group performance status of 1 presented with a one-month history of abdominal and back pain.Contrast-enhanced computed tomography revealed an infiltrative pancreatic head mass measuring 125×52×75 mm, with vascular involvement and multiple metastatic lymph nodes.Histopathological examination demonstrated RPC, with complete loss of nuclear SMARCB1 (INI1) expression by immunohistochemistry. Comprehensive next-generation sequencing showed KRAS wild-type status.The patient received modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) chemotherapy and achieved partial regression of metastatic abdominal lymph nodes after six cycles.Treatment was continued for a total of 12 cycles before disease progression was documented.This case highlights the aggressive clinical behavior and distinctive molecular profile of SMARCB1 (INI1)-deficient RPC.The observed partial response to mFOLFIRINOX suggests that selected patients may derive temporary benefit from systemic chemotherapy; however, durable disease control remains challenging.Increased recognition of this rare entity and further investigation of molecularly targeted and immunotherapeutic strategies are needed to improve outcomes.
2026-08-07 | RNA methyltransferase 3 drives pancreatic acinar cell carcinoma growth and is a therapeutic target.
Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m⁶A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter. Comprehensive analyses included m⁶A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and transforming growth factor-β signaling. METTL3 also promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting the clinical development of METTL3 inhibitors for ACC treatment.
2026-08-16 | [177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial.
In the phase 3 NETTER-2 study, first-line [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) significantly improved progression-free survival in patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Median progression-free survival was 22·8 months (95% CI 19·4-not estimable [NE]) with 177Lu-DOTATATE vs 8·5 months (7·7-13·8) in the control arm. Here, we report subgroup analyses, including preplanned assessments of efficacy by NET grade (G) and site of origin; further post-hoc analyses are reported in the main text. In this open-label, parallel-group study, patients from nine countries were randomised 2:1 to receive four cycles of 177Lu-DOTATATE plus octreotide long-acting repeatable (LAR) 30 mg every 8 weeks then octreotide LAR 30 mg every 4 weeks, or high-dose octreotide LAR 60 mg every 4 weeks. The primary endpoint (progression-free survival) was previously reported. Tumours were assessed at baseline, week 16, week 24, then every 12 weeks until disease progression or death. Preplanned subgroup analyses used blinded independent centrally reviewed data. The study is registered with ClinicalTrials.gov, NCT03972488, and is completed. Between Jan 22, 2020, and Oct 13, 2022, 261 patients were screened; 35 were excluded due to screen failure, and 226 were randomised. 177Lu-DOTATATE (n = 151) reduced risk of disease progression/death vs control (n = 75) regardless of NET grade/origin (hazard ratio [95% CI]: G2 NET 0·31 [0·18-0·53]; G3 NET 0·27 [0·14-0·49]; pancreatic NET 0·34 [0·20-0·56]; gastrointestinal NET 0·23 [0·12-0·46]). Median progression-free survival in months (95% CI) with 177Lu-DOTATATE was: G2 NET 29·0 (21·8-NE); G3 NET 22·2 (13·9-27·8); pancreatic NET 19·4 (16·6-24·9); gastrointestinal NET NE (22·6-NE). 177Lu-DOTATATE improved objective response rate vs control regardless of NET grade/origin. These findings support the use of first-line 177Lu-DOTATATE for patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive GEP-NETs, and for whom chemotherapy is not considered the most appropriate treatment option, regardless of NET grade (2/3) or origin (pancreas/gastrointestinal). Advanced Accelerator Applications, a Novartis Company.
2026-08-14 | Clinical, genomic, and spatial transcriptomic features of pancreatic adenosquamous carcinoma support subtype-specific therapeutic strategies.
Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to conventional pancreatic ductal adenocarcinoma (PDAC). This study aimed to characterize the clinical outcomes, genomic landscape, and spatial transcriptomic architecture of ASQ. We retrospectively evaluated clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (n=178). Genomic landscapes of ASQ (n=244) versus PDAC (n=29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n=11 from 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). ASQ patients had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (MSI-high, PD-L1+, TMB ³10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, while distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche. Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.
2026-08-13 | Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).
Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in ~ 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates-the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)-and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.
2026-08-07 | SMARCB1 (INI1)-deficient Rhabdoid Pancreatic Carcinoma: A Rare Subtype of Pancreatic Cancer
Rhabdoid pancreatic carcinoma (RPC) is a rare and highly aggressive subtype of undifferentiated pancreatic carcinoma characterized by rhabdoid morphology and frequent loss of SWItch/sucrose non-fermentable chromatin-remodeling complex-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), integrase interactor 1 (INI1) expression.Due to its rarity, its clinicopathological characteristics and optimal management remain poorly defined.A 56-year-old woman with an Eastern Cooperative Oncology Group performance status of 1 presented with a one-month history of abdominal and back pain.Contrast-enhanced computed tomography revealed an infiltrative pancreatic head mass measuring 125×52×75 mm, with vascular involvement and multiple metastatic lymph nodes.Histopathological examination demonstrated RPC, with complete loss of nuclear SMARCB1 (INI1) expression by immunohistochemistry. Comprehensive next-generation sequencing showed KRAS wild-type status.The patient received modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) chemotherapy and achieved partial regression of metastatic abdominal lymph nodes after six cycles.Treatment was continued for a total of 12 cycles before disease progression was documented.This case highlights the aggressive clinical behavior and distinctive molecular profile of SMARCB1 (INI1)-deficient RPC.The observed partial response to mFOLFIRINOX suggests that selected patients may derive temporary benefit from systemic chemotherapy; however, durable disease control remains challenging.Increased recognition of this rare entity and further investigation of molecularly targeted and immunotherapeutic strategies are needed to improve outcomes.
2026-08-07 | RNA methyltransferase 3 drives pancreatic acinar cell carcinoma growth and is a therapeutic target.
Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m⁶A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter. Comprehensive analyses included m⁶A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and transforming growth factor-β signaling. METTL3 also promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting the clinical development of METTL3 inhibitors for ACC treatment.
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Drug Discovery Landscape
1 orphan drug designation for Rare pancreatic disease, including 1 approved therapy.
1 orphan drug designation for Rare pancreatic disease, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Synthetic porcine secretin [Secreflo] | peptides | FDA | 2000-03-07 | 2002-04-04 | ChiRhoClin, Inc. |
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