Pazopanib

證據等級: L5

預測適應症: 10 個

Using the drug-repurposing report template directly (no specialized skill matches this content-generation task — it's a straightforward structured-writing job with the full spec already given in the prompt). One note before the report: this Evidence Pack is unusual in that it contains 10 predicted indications for Pazopanib rather than one, and original_indications/original_moa/Finland licensing are all empty (candidate is not yet marketed in Finland). I've adapted the template to surface the strongest candidate as the headline while still faithfully reporting the other nine, rather than mechanically reporting only predicted_indications[0] (Xp11.2-translocation RCC), which has zero supporting trials or literature — reporting it alone would understate what the pack actually shows (Dermatofibrosarcoma Protuberans has the only "Proceed with Guardrails" call, backed by a dedicated multicenter Phase 2 trial).

Pazopanib: From Renal Cell Carcinoma / Soft Tissue Sarcoma to Dermatofibrosarcoma Protuberans (and Other Rare Tumor Indications)

One-Sentence Summary

Pazopanib is an oral multi-target tyrosine kinase inhibitor (VEGFR-1/2/3, PDGFR-α/β, c-Kit) whose established oncology use — referenced throughout this evidence pack's trial context — is advanced renal cell carcinoma and non-adipocytic soft tissue sarcoma. Across 10 TxGNN-predicted indications evaluated here, the strongest signal is Dermatofibrosarcoma Protuberans (DFSP), supported by a dedicated multicenter Phase 2 trial (published, PMID 32956651) plus a second Phase 2a trial and case-level evidence; several other candidates (unclassified RCC, liposarcoma, fibroblastic neoplasm/desmoid-SFT) show moderate real-world and Phase 2 signal, while the remaining candidates are model-prediction-only with no supporting studies.

Quick Overview

Item	Content
Original Indication	Not recorded in this evidence pack (Finland: unmarketed, 0 licenses on file). Trial context within the pack points to advanced/metastatic renal cell carcinoma and non-adipocytic soft tissue sarcoma as the established indications elsewhere.
Predicted New Indication (headline)	Dermatofibrosarcoma Protuberans (rank 10 of 10 by TxGNN score, but strongest evidence tier)
TxGNN Prediction Score	99.29% (0.9929)
Evidence Level	L2
Finland Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails (for DFSP specifically — see per-indication breakdown below)

All 10 predicted indications at a glance:

Rank	Disease	TxGNN Score	Evidence Level	Decision Stage	Recommendation
1	RCC with Xp11.2/TFE3 fusion	99.63%	L5	S0	Hold
2	RCC associated with neuroblastoma	99.63%	L5	S0	Hold
3	Unclassified renal cell carcinoma	99.63%	L2	S2	Research Question
4	Liposarcoma	99.59%	L2	S2	Research Question
5	Childhood kidney cell carcinoma	99.54%	L4	S0	Hold
6	Ovarian myxoid liposarcoma	99.51%	L5	S0	Hold
7	Heart fibrosarcoma	99.37%	L4	S0	Hold
8	Fibroblastic neoplasm	99.35%	L2	S2	Research Question
9	Kidney fibrosarcoma	99.33%	L5	S0	Hold
10	Dermatofibrosarcoma protuberans	99.29%	L2	S3	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed mechanism-of-action data from DrugBank is not available in this evidence pack (flagged as a High-severity data gap, DG002). Based on information embedded in the trial and rationale records, Pazopanib is consistently described as a multi-target tyrosine kinase inhibitor acting on VEGFR-1/2/3, PDGFR-α/β, and c-Kit, with its established efficacy built on anti-angiogenic and anti-PDGFR activity in vascular- and PDGFR-driven tumors (renal cell carcinoma and non-adipocytic soft tissue sarcoma).

Dermatofibrosarcoma Protuberans (headline indication) is driven by the COL1A1-PDGFB fusion gene, which constitutively activates PDGFR signaling — the same pathway pazopanib inhibits, and the same logic that already supports imatinib's approved use in DFSP. This is a direct, mechanistically tight rationale rather than a broad tumor-type analogy, and it is the only indication in this pack with a purpose-built, published multicenter Phase 2 trial.

Several of the other candidates share a common thread: PDGFR- or VEGF-pathway-dependent mesenchymal tumors (liposarcoma, fibroblastic neoplasm/desmoid tumors and solitary fibrous tumor, non-clear-cell/unclassified RCC). These represent a coherent "class effect" hypothesis — pazopanib's known anti-angiogenic/anti-PDGFR activity extending across histologically related but formally distinct tumor types — and are backed by real-world cohorts and, in some cases, single-arm Phase 2 trials, but lack confirmatory randomized Phase 3 data. By contrast, the remaining candidates (Xp11.2/TFE3-fusion RCC, RCC associated with neuroblastoma, childhood kidney cell carcinoma, ovarian myxoid liposarcoma, heart fibrosarcoma, kidney fibrosarcoma) are extremely rare pathological entities with no direct trials or literature; two of them (childhood kidney cell carcinoma, heart fibrosarcoma) appear to reflect ontology/label mismatches — their only linked trials concern adult metastatic RCC and generic non-rhabdomyosarcoma soft tissue sarcoma populations, not the specific rare entity named.

Clinical Trial Evidence — Dermatofibrosarcoma Protuberans

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01059656	Phase 2a	Terminated	23	Multicenter trial of pazopanib in unresectable, locally advanced/metastatic DFSP, based on PDGF pathway activation via the COL1A1-PDGFB fusion gene; terminated early but provides direct prospective data.
NCT02180867	Phase 2/3	Active, not recruiting	140	Preoperative chemoradiation ± pazopanib in non-rhabdomyosarcoma soft tissue sarcoma (NRSTS); may include DFSP cases but not subtype-specific.
NCT06239272	Phase 1/2	Recruiting	139	Risk-adapted maintenance pazopanib + dose-escalated radiation ± selinexor in NRSTS; broad population, not DFSP-specific.
NCT02601209	Phase 1/2	Terminated	151	Sapanisertib (TAK-228) vs. pazopanib in locally advanced/metastatic sarcoma; terminated, low direct relevance to DFSP.

Literature Evidence — Dermatofibrosarcoma Protuberans

PMID	Year	Type	Journal	Key Findings
32956651	2021	Multicenter Phase 2 trial	J Invest Dermatol	Dedicated Phase 2 study of pazopanib in unresectable DFSP; evaluates efficacy/safety in a population where imatinib (also PDGFR-targeted) has established 36–80% response rates.
37610680	2023	Translational (PDX/cell line)	Human Cell	Multi-omic profiling of imatinib-resistant DFSP with fibrosarcomatous transformation; relevant to sequencing pazopanib after imatinib failure.
34066400	2021	Cohort	Cancers	Long-term outcomes of neoadjuvant TKI (imatinib or pazopanib) followed by surgery in locally advanced DFSP (n=27, 9 with fibrosarcomatous transformation).
28515919	2017	Translational/pathology	Mol Clin Oncol	PD-L1 expression associated with fibrosarcomatous transformation of DFSP; case-level molecular context.
27988943	2017	Case report	J Dermatol	Partial response to pazopanib in metastatic fibrosarcomatous DFSP without genetic translocation, refractory to prior chemotherapy regimens.
27434055	2016	Review	Cancer	General chemotherapy review for soft tissue sarcoma, contextualizing pazopanib's place among treatment options.
24555529	2014	Review	Expert Rev Anticancer Ther	Emerging therapies for adult soft tissue sarcoma, including pazopanib.
24712007	2014	Review	Magy Onkol	Histological-subtype-based medical treatment of soft tissue sarcomas.
22510939	2012	Review	Curr Opin Oncol	Review of PDGFR-inhibitor clinical trial results specifically in DFSP.
37592448	2023	Functional/fusion-gene screen	Cancer Sci	Screen of 59 sarcoma fusion genes identifying pazopanib as a potential inhibitor of the COL1A1-PDGFB fusion gene specifically.

Additional Predicted Indications with Research-Level Evidence (L2, "Research Question")

These three candidates did not reach the "Proceed with Guardrails" bar but have meaningfully more than model-prediction-only support and may warrant monitoring or future re-evaluation.

Liposarcoma (TxGNN score 99.59%)

Rationale caveat: pazopanib's approved soft tissue sarcoma indication (PALETTE trial) explicitly excludes adipocytic sarcomas, so this is a "reversal of an exclusion" hypothesis specifically requiring independent validation — not a simple label extension.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01506596	Phase 2	Completed	42	Single-agent pazopanib in unresectable/metastatic liposarcoma — direct, subtype-specific.
NCT01532687	Phase 2 (randomized, double-blind)	Completed	54	Gemcitabine ± pazopanib in refractory soft tissue sarcoma — direct comparison including liposarcoma patients.
NCT06263231	Phase 3	Active, not recruiting	333	INT230-6 (intratumoral) vs. US standard of care in liposarcoma/UPS/leiomyosarcoma — background reference only (non-pazopanib arm).
NCT02180867	Phase 2/3	Active, not recruiting	140	Pazopanib neoadjuvant trial in NRSTS, may include liposarcoma subtypes.
NCT01692496	Phase 2	Completed	52	Pazopanib activity/tolerability in advanced/metastatic liposarcoma after relapse.

PMID	Year	Type	Journal	Key Findings
31010343	2019	Phase 2 trial report	Expert Opin Investig Drugs	Pazopanib in advanced intermediate/high-grade liposarcoma.
28832986	2017	Prospective Phase 2	Cancer	Prospective Phase 2 study of pazopanib in advanced intermediate/high-grade liposarcoma.
33355646	2021	Randomized Phase 2 (PAPAGEMO)	JAMA Oncol	Pazopanib ± gemcitabine in anthracycline/ifosfamide-refractory soft tissue sarcoma.
25500074	2014	Preclinical (xenograft)	Transl Oncol	Pazopanib suppresses tumor growth via anti-angiogenesis in dedifferentiated liposarcoma xenograft models.
30060824	2018	Case report (PDOX model)	Tissue Cell	PDGFRA-amplified pleomorphic liposarcoma regressed by pazopanib in a patient-derived orthotopic xenograft.

Unclassified Renal Cell Carcinoma (TxGNN score 99.63%)

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01613846	Phase 3	Completed	544	Sorafenib→pazopanib vs. pazopanib→sorafenib sequencing in advanced/metastatic RCC (sorafenib-led trial; indirect reference only).

PMID	Year	Type	Journal	Key Findings
28546525	2018	Phase 2 single-arm trial	Cancer Res Treat	Direct Phase 2 evaluation of pazopanib in metastatic non-clear-cell RCC.
28108284	2017	Retrospective multicenter (PANORAMA)	Clin Genitourin Cancer	First-line pazopanib in non-clear-cell RCC, Italian multicenter cohort.
27568124	2017	Retrospective cohort	Clin Genitourin Cancer	Outcomes of metastatic non-clear-cell RCC patients treated with pazopanib.
31921344	2019	Real-world cohort	Ecancermedicalscience	Sunitinib vs. pazopanib interchangeability in non-clear-cell/sarcomatoid mRCC.

Fibroblastic Neoplasm (desmoid tumor / solitary fibrous tumor spectrum, TxGNN score 99.35%)

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02066285	Phase 2	Completed	96	Single-agent pazopanib in solitary fibrous tumor and extraskeletal myxoid chondrosarcoma — direct, subtype-specific.
NCT02180867	Phase 2/3	Active, not recruiting	140	Pazopanib neoadjuvant NRSTS trial, may include fibroblastic subtypes.

PMID	Year	Type	Journal	Key Findings
30578023	2019	Multicentre single-arm Phase 2	Lancet Oncol	Pazopanib for advanced malignant/dedifferentiated solitary fibrous tumor.
25269954	2014	Preclinical + clinical case evidence	Eur J Cancer	Preclinical and clinical activity of pazopanib in solitary fibrous tumor.
38759389	2024	Real-world multicenter cohort (CanSaRCC)	Eur J Cancer	Pazopanib and sorafenib real-world experience in desmoid tumors.
29384266	2018	Cohort (AYA patients)	Pediatr Blood Cancer	Pazopanib therapy for desmoid tumors in adolescent/young adult patients.
29614488	2018	Retrospective cohort	Oncology	Efficacy/safety of pazopanib for recurrent/metastatic solitary fibrous tumor.

Low-Evidence Indications (L4–L5, "Hold")

The remaining six candidates have no subtype-specific trials or literature, or only indirect/mismatched trial linkage. They are not recommended for further action at this time.

Disease	Evidence Level	Key Issue
RCC with Xp11.2/TFE3 fusion	L5	No trials/literature; MiT-family translocation RCC typically shows poor response to VEGF-TKIs in general literature.
RCC associated with neuroblastoma	L5	Extremely rare secondary malignancy entity; no direct evidence, pure class-analogy reasoning.
Childhood kidney cell carcinoma	L4	Only linked trial (NCT01575548) is an adult metastatic RCC Phase 3 registration trial — likely an ontology/label mapping error; no pediatric safety/PK data.
Ovarian myxoid liposarcoma	L5	Myxoid liposarcoma is characteristically an extremity tumor; ovarian primary site is an extremely rare presentation with no direct evidence.
Heart fibrosarcoma	L4	Linked trials are generic NRSTS studies (one terminated); no cardiac-site-specific data; anti-angiogenic cardiotoxicity risk adds complexity.
Kidney fibrosarcoma	L5	No trials/literature; extremely rare entity, pure class-analogy reasoning.

Finland Market Information

Pazopanib does not currently hold a marketing authorization in Finland (0 licenses on file; market status: not marketed). No product/dosage-form table is available from this evidence pack.

Cytotoxicity

Pazopanib is an antineoplastic agent per its use in this evidence pack (renal cell carcinoma, soft tissue sarcoma, and the sarcoma-family indications evaluated above), but it is a targeted small-molecule kinase inhibitor, not a conventional cytotoxic chemotherapy agent.

Item	Content
Cytotoxicity Classification	Targeted therapy — multi-target tyrosine kinase inhibitor (VEGFR-1/2/3, PDGFR-α/β, c-Kit)
Myelosuppression Risk	Not specified in this evidence pack (DrugBank toxicity data not available). As monotherapy, generally lower myelosuppressive burden than conventional cytotoxics; risk increases materially in combination regimens seen in the trial evidence above (e.g., gemcitabine + pazopanib). Please refer to the package insert for confirmed hematologic toxicity data.
Emetogenicity Classification	Please refer to the package insert warnings and precautions
Monitoring Items	Please refer to the package insert warnings and precautions
Handling Protection	Please refer to the package insert warnings and precautions

Safety Considerations

Please refer to the package insert for safety information. (Key warnings, contraindications, and drug interaction data are all flagged as data gaps in this evidence pack — notably DG001, a Blocking-severity gap for TFDA/Fimea package-insert warnings and contraindications, which currently prevents this candidate from entering the S1 safety pre-screen stage.)

Conclusion and Next Steps

Decision: Proceed with Guardrails (candidate-level, driven by Dermatofibrosarcoma Protuberans; other indications carry differentiated, lower-tier recommendations — see summary table above)

Rationale:

Dermatofibrosarcoma Protuberans has a mechanistically direct rationale (COL1A1-PDGFB fusion → PDGFR dependence) and a dedicated, published multicenter Phase 2 trial (PMID 32956651) plus a second prospective Phase 2a trial — the only indication in this pack reaching decision stage S3.
Liposarcoma, unclassified RCC, and fibroblastic neoplasm/desmoid-SFT show real Phase 2 and real-world cohort signal (L2) but lack confirmatory Phase 3 data and, in liposarcoma's case, actively contradict pazopanib's current approved-indication exclusion — these remain open research questions rather than actionable candidates.
The remaining six candidates (Xp11.2/TFE3-fusion RCC, RCC with neuroblastoma, childhood kidney cell carcinoma, ovarian myxoid liposarcoma, heart fibrosarcoma, kidney fibrosarcoma) have no direct supporting evidence and, in two cases, show signs of disease-ontology mapping errors; they should be held pending re-verification of the TxGNN disease labels against source ontologies.

To proceed, the following is needed:

Blocking: Obtain the TFDA/Fimea package insert (warnings, contraindications) — this evidence pack cannot complete the S1 safety pre-screen without it (DG001).
High priority: Confirm mechanism of action via DrugBank API to validate the mechanistic-link reasoning used throughout this report (DG002).
Re-verify disease ontology mapping for "childhood kidney cell carcinoma" and "heart fibrosarcoma," where the only linked trials describe unrelated adult/generic populations.
Complete route-of-administration compatibility checks (all route_compatibility.status fields are currently "pending" in this pack) before any go-forward indication proceeds past S3.
For DFSP specifically: obtain post-2021 follow-up data or additional trial results, since the pivotal Phase 2 trial (PMID 32956651) and the earlier Phase 2a trial (NCT01059656, terminated) remain the only subtype-specific prospective evidence.
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.