1. Overview of WT1: Biology and Structure

WT1 (Wilms Tumor 1) is a zinc finger transcription factor encoded on chromosome 11p13, originally described as a tumor suppressor in pediatric nephroblastoma. However, its function is far more complex: depending on the cellular context, WT1 can act as an oncogene or a tumor suppressor. It regulates gene transcription, cellular differentiation, and organogenesis during development, and maintains homeostasis in adult tissues.

WT1 produces multiple isoforms (+KTS, –KTS) through alternative splicing, each playing distinct roles in gene expression and tumor biology. Its expression is typically restricted to embryonic and select adult tissues like kidney podocytes, but is aberrantly upregulated in a wide array of cancers.

2. Hematologic Malignancies and WT1

a) Acute Myeloid Leukemia (AML)

WT1 is mutated in ~15% of AML patients and often co-mutated with FLT3-ITD or NPM1. These mutations influence the Wnt/β-catenin, TET2, and MEG3 pathways, promote leukemogenesis, and impact response to chemotherapy. WT1 overexpression enhances stemness, self-renewal, and resistance to apoptosis.

b) Myelodysplastic Syndromes (MDS)

WT1 is overexpressed in ~50% of MDS patients. It is associated with poor prognosis and disease progression. WT1 interacts synergistically with FLT3 mutations, contributing to transformation to AML.

c) T-cell Acute Lymphoblastic Leukemia (T-ALL)

WT1 mutations (~10% of T-ALL cases) activate the IL7R-JAK-STAT pathway and impair TP53-mediated DNA damage response. Co-occurrence with NOTCH1/FBXW7/FLT3 mutations suggests an oncogenic synergy.

d) Chronic Myeloid Leukemia (CML)

WT1 expression is increased in advanced CML via BCR-ABL1 activation. It contributes to resistance against tyrosine kinase inhibitors like imatinib by interfering with apoptosis and gene regulation through the WT1/ZNF224/c-Myc axis.

e) Acute Promyelocytic Leukemia (APL)

WT1 interacts with the PML-RARA fusion protein, altering differentiation. Noncoding mutations in WT1 may also contribute to leukemogenesis.

3. WT1 in Solid Tumors

a) Lung Cancer

WT1 promotes VEGF isoform expression and angiogenesis. It may serve as a target to reverse resistance to EGFR inhibitors in non-small-cell lung cancer (NSCLC).

b) Breast Cancer

WT1 isoforms have distinct roles in ER-positive and triple-negative breast cancer. They affect ERα signaling, promote EMT and metastasis, and may predict resistance to hormone therapy. WT1-targeted vaccines in combination with endocrine therapy show promising early results.

c) Neuroblastoma

In neuroblastoma, WT1 often functions as a tumor suppressor. It promotes differentiation through inhibition of PI3K/Akt and MAPK/ERK pathways. However, high WT1 is paradoxically associated with poor prognosis in non-MYCN-amplified tumors.

d) Prostate Cancer

WT1 downregulates E-cadherin, facilitating migration and metastasis. It also modulates VEGF transcription and androgen receptor activity, influencing hormone resistance.

e) Hepatocellular and Pancreatic Cancer

WT1 influences Wnt/β-catenin, JAK2/STAT3, and NF-κB pathways. It promotes tumorigenesis, invasion, and modulates immune escape mechanisms. In pancreatic ductal adenocarcinoma, it interacts with STAT3 and miR-216a/KRT7, facilitating metastasis.

f) Ovarian Cancer

WT1 is highly expressed in serous subtypes and promotes EMT via ERK1/2 and E-calmodulin pathways. It is involved in mesenchymal–epithelial transitions (MET) and cancer stem cell formation through interaction with EZH2.

g) Astrocytomas/Glioblastoma

WT1 contributes to glioblastoma aggressiveness and poor prognosis. Its inhibition enhances radiosensitivity, and WT1 vaccines elicit cytotoxic immune responses in glioma patients.

4. WT1 as a Therapeutic Target

a) Chemical Inhibitors

Agents like 17-AAG (Hsp90 inhibitor), TMPyP4 (G-quadruplex stabilizer), and daunorubicin reduce WT1 expression. These agents inhibit tumor growth and increase chemosensitivity in WT1-overexpressing malignancies.

b) Natural Products

Compounds such as bufalin, shikonin, aloin, curcumin, and resveratrol suppress WT1 expression and modulate apoptosis pathways. Marine-derived molecules also show potential in WT1 inhibition.

c) Kinase Modulators

GSK3β affects WT1 stability and degradation. Dasatinib is proposed as a modulator to reduce cytokine release syndrome in combination therapies.

5. Immunotherapy Strategies

• Peptide Vaccines: WT1-derived peptides induce T-cell and humoral responses; trials show tolerability and clinical activity in AML and glioblastoma.
• Dendritic Cell Vaccines: Boost CD8+ T-cell responses; combination with chemotherapy improves remission rates.
• Bispecific Antibodies: T-cell engaging antibodies (e.g., ESK1-BiTE) target WT1 in HLA-A*02:01 context.
• TCR Gene Therapy: Autologous T cells engineered to express WT1-specific TCRs show persistence and safety in early-phase trials.

Conclusion and Future Prospects

WT1 is a compelling, dual-role protein in cancer biology. It functions as a context-dependent oncogene or tumor suppressor, modulating multiple pathways in both hematologic and solid tumors. Its overexpression correlates with treatment resistance and poor prognosis.

Targeting WT1 is now a key area of translational research, with therapeutic strategies spanning small molecules, natural products, and immunotherapies. Though many approaches remain in preclinical or early clinical stages, the diversity of mechanisms through which WT1 drives cancer supports its status as a pan-cancer therapeutic target.

Comprehensive Summary

This narrative review explores the evolution of personalized medicine in the context of Wilms tumor (WT), the most common renal malignancy in children. It synthesizes recent advancements in molecular diagnostics, risk stratification, and therapeutic innovations, offering a roadmap for the development of individualized care pathways in pediatric oncology.

1. Background and Rationale

Wilms tumor accounts for roughly 7% of all childhood cancers, with a high survival rate (>90%) for localized disease in developed countries. However, variability in outcomes persists due to biological heterogeneity, socioeconomic disparities, and treatment-related toxicity. The shift toward risk-adapted and genetically-informed strategies is positioned as key to improving outcomes while minimizing late effects.

2. Genetic and Molecular Foundations

Key genetic players such as WT1, CTNNB1, SIX1, MYCN, and WTX are central to WT pathogenesis. The review emphasizes that:

• WT1 mutations are highly predictive of prognosis, especially in bilateral disease.
• SIX2 expression, DNA methylation profiles, and circulating miRNAs (e.g., miR-144-3p) provide non-invasive biomarkers.
• Mutations in DIS3 and TERT are noted in relapsed WT, underlining the evolution of tumor biology over time.

3. Diagnostics: Beyond Morphology

The authors advocate for integrating imaging, molecular, and epigenetic data to enable early detection and treatment personalization:

• Ultrasound, MRI, and CT remain standard imaging tools, but now enhanced with radiomics and 3D segmentation.
• Liquid biopsies, including ddPCR for PIK3CA mutations in urine/plasma, offer a minimally invasive route to real-time monitoring.
• Genomic and transcriptomic tools provide detailed tumor profiling, now entering routine clinical pipelines.

4. Risk Stratification and Prognostic Modeling

The review underscores a paradigm shift from stage-based to biomarker-based stratification:

• Tumor volume, while still a classical metric, gains predictive power when integrated with molecular profiles.
• Nomograms using multi-omic and clinical data help forecast recurrence, survival, and therapy response.
• Machine learning models incorporating radiomics, genomics, and clinical data are under development to support decision-making.

5. Therapeutic Innovations and Personalization
6. a) Standard Therapy with Personalization

• Traditional agents (vincristine, actinomycin D, doxorubicin) remain effective, but dose and duration are increasingly adjusted based on molecular risk.
• Nephron-sparing surgery and preoperative chemotherapy are optimized using volumetric and genetic data.

1. b) Targeted Therapies

• HIF-2α inhibitors and IGF-1R pathway blockers are in trials for treatment-resistant cases.
• Targeting the Wnt/β-catenin and AKT pathways is a key focus.

1. c) Immunotherapy

• WT1 peptide vaccines, immune checkpoint inhibitors (PD-1/PD-L1), and CAR-T cells are emerging options, especially for relapsed/refractory WT.
• Combining WT1 vaccines with HLA-matched peptides enhances immune targeting with early evidence of improved outcomes.

1. d) Genetic and Epigenetic Interventions

• Techniques such as CRISPR-Cas9, RNA interference, and methylation modulators are in early-phase development.
• These strategies aim to reverse tumor-promoting gene expression and reduce resistance mechanisms.

6. Radiomics and Advanced Imaging

The review details how radiomic analysis and AI-assisted imaging can predict histological subtypes, therapeutic response, and relapse risk. Coupled with genomic data, they provide the basis for integrative predictive models that will soon guide both surgical planning and post-treatment surveillance.

7. Global Collaboration and Equity in Care

• The authors call for international cooperation to validate predictive models and ensure equitable access to genomic testing and targeted therapies.
• Socioeconomic disparities must be addressed to democratize personalized medicine, particularly in resource-limited settings.

8. Future Directions and Framework Proposal

The authors propose a multi-dimensional predictive framework based on:

1. Next-generation sequencing (NGS) for WT1/CTNNB1/WTX
2. Epigenomic profiling for methylation and histone changes
3. Transcriptomic analysis (e.g., RNA-seq)
4. Radiomic features from diffusion-weighted MRI
5. Integrated AI models for real-time decision support
6. Clinical teams trained in data interpretation and continuous feedback updating from registries

Conclusion

This review establishes that the future of WT therapy lies in personalization. By integrating multi-omic diagnostics, predictive modeling, and innovative therapies, clinicians can move toward tailoring care to the individual child. These efforts promise not only higher survival, but also reduced toxicity, better quality of life, and long-term survivorship.

Comprehensive Summary

This retrospective audit analyzes 23 pediatric Wilms’ tumor (WT) cases managed at a single Indian tertiary-care center over a 3-year period (2021–2024). The study evaluates how SIOP Umbrella protocols were applied and adapted in a resource-limited setting, offering insights into protocol adherence, surgical approaches, tumor response, immunohistochemistry, and outcomes in unilateral and bilateral WT.

1. Patient Demographics and Study Design

• Total patients: 23 (19 unilateral WT [uWT], 4 bilateral WT [bWT])
• Median age: 36 months
• Male:Female ratio: 2.3:1
• Data sources: Medical records, imaging, core-needle biopsy (CNB), histopathology, immunohistochemistry (IHC)
• Ethical approval obtained; study focused only on de novo cases treated in-house

2. Diagnostics and Protocol Deviations

• CNB performed in 22/23 patients pre-therapy, including IHC for WT1, p53, and Ki-67
• Despite SIOP-RTSG discouraging routine CNB, it was performed routinely here due to the higher incidence of non-Wilms renal tumors (15–20%) in South Asia
• All patients, except one neonate, received neoadjuvant chemotherapy (NACT)
• Tumor volumetry (via CECT): median pre-NACT tumor volume = 1023 mL, post-NACT = 612 mL
• Tumor shrinkage seen in 61%, stable/increased in 39% – volume reduction was not predictive of outcome

3. Surgical Management

• Nephroureterectomy in 17 renal units
• Nephron-sparing surgery (NSS) in 10 renal units (including in non-syndromic uWT and multifocal disease)
• NSS sometimes performed against Umbrella guidelines, particularly in tumors >300 mL
• NSS associated with better postoperative renal function, lower hypertension, and preserved renal mass
• No intraoperative tumor rupture (IOTR) occurred, despite several large tumors

4. Histopathology and Risk Stratification

• Intermediate risk histology: 21 patients (mixed, stromal, regressive, focal anaplasia)
• High risk: 2 patients (diffuse anaplasia, blastemal type)
• IHC findings:
  • WT1 positivity in 21/23
  • p53 mutations in 7/23
  • High Ki-67 (>70%) correlated with chemoresistance and poor prognosis
• Low Ki-67 + p53 mutation often predicted poor NACT response

5. Chemotherapy, Radiation, and Supportive Care

• Adjuvant chemotherapy completed in 18 patients, 2 on treatment
• Flank radiation used in 6 patients
• Multidisciplinary care included free lodging, nutrition, and counseling (“Home Away from Home” model)
• In-patient chemotherapy reduced abandonment risk
• Despite lacking in-house radiotherapy, radiation was started within 10 days post-op via national network

6. Recurrences and Metastases

• Four patients had metastatic WT at diagnosis: 2 with pulmonary, 2 with liver metastasis
• Pulmonary metastases were managed with chemotherapy ± bilateral metastatectomy
• Liver metastasis had worse outcomes, including one metachronous recurrence post-treatment
• Two recurrences occurred locally (renal bed); both patients survived after multimodal therapy

7. Outcomes and Survival Analysis

• 1-year overall survival (OS): 84%
• 1-year event-free survival (EFS): 76%
• 2-year OS: 77%
• 2-year EFS: 76%
• For localized uWT (Stages I–III), 2-year OS and EFS reached 100% and 93%, respectively
• Outcomes for Stage IV and bWT remain poor, mirroring national data

8. Discussion and Strategic Insights

• Switching from upfront surgery to SIOP-based neoadjuvant chemotherapy dramatically improved outcomes, particularly in reducing IOTR and relapses
• Challenges remain in identifying non-responders to NACT, particularly those with stromal or blastemal histology
• Systematic use of CNB and IHC helps in pre-treatment risk identification, albeit controversial
• The use of centralized support services, early multidisciplinary planning, and enhanced follow-up are crucial for optimal outcomes in LMICs
• Despite limitations, the center matched short-term outcomes from high-income countries for localized WT