Linsitinib (OSI-906; Astellas) is a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of both insulin-like growth factor 1 receptor (IGF1R; IC50 ~35 nM) and the insulin receptor (IR; IC50 ~75 nM). By blocking the shared kinase activation loop, linsitinib prevents IGF2-driven transautophosphorylation of IGF1R/IR-A and the downstream phosphorylation of IRS1/IRS2, PI3K/p85, and ultimately AKT and ERK — blocking the mitogenic and survival cascade driven by autocrine/paracrine IGF2. The mechanistic rationale in SDH-deficient tumours rests on two reinforcing pathways that both converge on IGF2 overexpression: **Pathway 1 — Pseudohypoxia (HIF-driven IGF2 transcription):** SDH loss → succinate accumulation → competitive inhibition of PHD2/PHD3 prolyl hydroxylases → VHL cannot target HIF-α for ubiquitin-mediated proteasomal degradation → constitutive HIF-1α/2α nuclear accumulation → HIF directly transcribes IGF2 via hypoxia-response elements (HREs) in the IGF2 promoter. This is the same pseudohypoxic HIF-1α/2α transcriptional program that drives VEGF, CAIX, GLUT1, and CXCR4 in SDH-deficient tumours — IGF2 is one of the major HIF target genes. **Pathway 2 — CIMP-driven loss of imprinting:** SDH loss → succinate → competitive inhibition of α-KG-dependent TET1/2/3 dioxygenases → impaired 5mC→5hmC conversion → DNA hypermethylation at CIMP loci (Letouzé et al. Cancer Cell 2013, PMID 23550148; Killian et al. Cancer Cell 2013, PMID 23707781) → methylation of the H19 imprinting control region (ICR) at chr11p15.5 → silencing of the H19 non-coding RNA repressor → de-repression of the adjacent IGF2 locus on the normally silenced maternal allele → biallelic IGF2 expression (loss of imprinting). Nielsen et al. (Endocr Relat Cancer 2015, PMID 26400872) confirmed this mechanism in adrenal tumours: H19 ICR hypermethylation correlated directly with IGF2 overexpression in 100% of pheochromocytomas analysed. **Convergence:** Both mechanisms operate simultaneously in SDH-deficient pseudohypoxic tumours, creating synergistic IGF2 overexpression. IGF2 binds IGF1R with high affinity and IR-A (the fetal insulin receptor isoform re-expressed in cancer) with moderate affinity → constitutive receptor activation → IRS1/IRS2 phosphorylation → PI3K/AKT/mTORC1/S6K1 (overlap with everolimus/capivasertib Mechanisms 4/27) and RAS/MAPK/ERK (proliferation) → tumour growth and survival. **Clinical anchor and negative data context:** Linsitinib was evaluated in a Phase 3 randomised, double-blind, placebo-controlled trial (NCT00924989; n=139; Fassnacht et al. Lancet Oncol 2015, PMID 25795408) in locally advanced or metastatic adrenocortical carcinoma (ACC) — a tumour type that, like SDH-deficient PPGL, is characterised by high-frequency IGF2 overexpression at chr11p15.5. The Phase 3 did not improve overall survival (median 323 days linsitinib vs. 356 days placebo; HR 0.94; p=0.77). This negative result is critical context and directly informs the evidence_score of 22 (theoretical) assigned here. **Key distinction between ACC and SDH-deficient PPGL context:** The ACC Phase 3 enrolled an unselected population (IGF2 expression level not used as an inclusion criterion, and not all ACCs overexpress IGF2 to the same degree). In SDH-deficient PPGL specifically, IGF2 overexpression is near-universal (100% in Nielsen et al. 2015 PCC cohort, PMID 26400872) and mechanistically enforced by two independent SDH-loss-driven pathways — making PPGL a more molecularly homogeneous IGF2-high target population than unselected ACC. Nonetheless, the negative Phase 3 in the nearest analogue tumour means single-agent IGF1R inhibition may be insufficient without concurrent biomarker stratification for IGF2 expression or combination strategies (e.g., with mTOR or MEK inhibitors to prevent signalling rebound). **Phase 1 pharmacology (PMID 25208878):** Jones et al. (Clin Cancer Res 2014, PMID 25208878) defined the MTD of linsitinib (600 mg once daily on intermittent schedules), confirmed IGF1R target engagement in peripheral blood mononuclear cells (reduced phospho-IGF1R), and documented 2 confirmed partial responses in ACC patients — providing proof-of-pharmacology in an IGF2-driven tumour. **Combination rationale:** IGF1R/IR inhibition blocks the upstream growth factor signal. Downstream mTOR inhibition (everolimus) addresses the same PI3K/AKT/mTOR node from below. The two strategies have complementary mechanisms and could prevent the feedback AKT re-activation seen with mTOR monotherapy: mTOR inhibition → S6K1 inhibition → loss of IRS1 serine phosphorylation (negative feedback) → IRS1 becomes hyperresponsive to IGF1R signalling → AKT reactivation; linsitinib upstream prevents this feedback by blocking IGF1R/IR-A kinase activity. **GIST-specific clinical trial — NEGATIVE Phase 2 (direct patient safety note for SDHA-deficient GIST):** Von Mehren et al. (Clin Cancer Res 2020, PMID 31792037) conducted a prospective NCI/SARC Phase 2 trial (NCT01560260; n=20 adult and paediatric WT-GIST patients, 35% SDHA IHC-negative, 88% SDHB IHC-negative — an SDH-deficient-enriched cohort). Primary endpoint: objective response rate = **0% (zero objective responses)**. Clinical benefit rate at 9 months: 40% (stable disease only, no confirmed partial or complete responses). This is the most directly relevant clinical trial for the SDHA-deficient GIST population and defines a hard ceiling on single-agent IGF1R inhibition in GIST. tumor_type_applicability is accordingly restricted to ["ppgl"] — the mechanistic case for SDH-deficient PPGL (near-universal IGF2 overexpression via dual HIF- and CIMP-driven pathways, both absent or less dominant in GIST) remains intact, but linsitinib is disqualified as a GIST option based on direct Phase 2 evidence. **Key limitation:** No published data test linsitinib or any IGF1R inhibitor in SDH-deficient PPGL or RCC cell lines or xenograft models. The mechanistic case rests on (1) Letouzé/Killian CIMP mechanism (PMIDs 23550148, 23707781), (2) Nielsen et al. universal PCC IGF2 overexpression (PMID 26400872), (3) Fassnacht et al. Phase 3 negative in ACC (PMID 25795408), and (4) Von Mehren et al. Phase 2 negative in WT/SDH-deficient GIST (PMID 31792037, NCT01560260). Both clinical trials failed to demonstrate objective responses. Evidence_score 22 (theoretical/low) reflects the strong mechanistic basis specifically for PPGL, the two negative clinical precedents, and the absence of PPGL-specific experimental or clinical trial data.