Targeted Therapy Involving Growth Factors

Targeted Therapy

Targeted therapy involving growth-factor pathways in adrenocortical carcinoma (ACC) refers to treatment strategies aimed at dysregulated ligand-receptor signaling networks, receptor tyrosine kinases, and tumor angiogenesis. Within ACC therapeutics, this area sits between broad cytotoxic therapy and more biomarker-defined precision oncology, drawing primarily on the IGF axis, EGFR/MAPK signaling, VEGF- and multikinase-directed approaches, and smaller exploratory programs involving FGFR or cMET.¹²

The biological rationale for these approaches is strong. ACC frequently shows activation of growth-factor programs, especially IGF2 overexpression and angiogenic signaling, and laboratory models have demonstrated pathway dependence in at least some tumors.³⁴ However, the clinical evidence remains limited by small retrospective series, nonrandomized phase 1 or 2 studies, basket trials with very small ACC subsets, and occasional case reports that may not generalize.⁵⁶⁷

Across pathways, a consistent finding is that pathway presence does not reliably predict pathway addiction. In unselected advanced ACC, single-agent targeted therapies have more often produced temporary disease stabilization than durable tumor regression, and negative or modest results have tempered early enthusiasm for several biologically plausible targets.³⁵¹ Interpretation is further complicated by mitotane, which may alter kinase-inhibitor exposure through CYP3A4 induction and can confound both efficacy and toxicity analyses in advanced-disease cohorts.⁷⁵

For this reason, growth-factor-directed therapy in ACC is best viewed as an active but still nondefinitive research domain rather than a uniformly established treatment class. The more reliable conclusions concern broad patterns—heterogeneous sensitivity, frequent cytostatic rather than cytoreductive effects, and the likely need for molecular selection or rational combinations—whereas claims for any single agent are often supported only by limited prospective data or isolated exceptional responses.¹⁸⁹

Diagnostic and Biological Context

ACC is a biologically heterogeneous endocrine malignancy in which proliferative and survival signaling may arise from multiple overlapping pathways rather than a single dominant driver. This helps explain why receptor expression or pathway activation observed in tissue studies has often translated imperfectly into treatment response.¹²

A recurring theme in the literature is the gap between mechanistic plausibility and clinical predictiveness. Preclinical models may identify signaling vulnerabilities, but these findings are not consistently reproduced in patients, especially when studies enroll unselected populations or combine ACC with other tumor types. The practical implication is that biomarker interpretation should remain cautious and should not be assumed to define treatment sensitivity without clinical validation.³¹⁰

IGF Axis

The IGF pathway has been the most prominent growth-factor target in ACC because IGF2 overexpression is a well-known feature of the disease and has long been linked to tumor biology. This made IGF1R inhibition an appealing therapeutic strategy and a model system for translational ACC research.³

Clinical experience, however, has suggested that IGF-directed therapy has limited activity in unselected patients. Early studies showed tolerability and occasional stable disease, but objective responses were uncommon, and the broader signal was one of cytostatic effect at best rather than consistent tumor shrinkage.³¹ This is one of the more reliable conclusions in the targeted-therapy literature: IGF pathway activation is common, but dependence appears variable. The practical implication is that IGF signaling remains useful for biological subclassing and combination hypotheses, but not as a validated stand-alone treatment selector.³

Because single-pathway blockade appears insufficient in many tumors, the IGF literature has also reinforced interest in combination strategies, including pairing pathway inhibition with mTOR or other downstream signaling approaches. Evidence for this remains suggestive rather than definitive, with most support coming from preclinical or early-phase settings rather than comparative ACC trials.¹¹

EGFR, MAPK, and Related Signaling

EGFR and downstream MAPK signaling have been investigated as adjacent receptor-kinase programs in ACC, but the clinical results have generally been underwhelming. Tissue expression and occasional pathway alterations suggest biological relevance, yet expression alone has not proven to be a reliable predictor of benefit.¹

Retrospective and early clinical evidence indicates that EGFR-directed therapy has shown little meaningful activity in refractory ACC, particularly when used without molecular enrichment. What is more reliable here is the negative lesson: overexpression should not be equated with therapeutic dependence. The practical implication is that EGFR-targeted treatment is not established in routine ACC care, although EGFR may still matter as part of combinatorial pathway biology.¹

This leads into a broader principle seen across RTK-directed studies: escape signaling and pathway cross-talk may limit single-agent efficacy. In ACC research, EGFR/MAPK signaling is therefore more relevant as a potential resistance circuit or co-targeting opportunity than as a clearly validated monotherapy target.

Angiogenesis, VEGFR, and Multikinase Inhibitors

Angiogenesis-targeted therapy has produced the most visible clinical signal among growth-factor-directed approaches in ACC. Multiple lines of biological evidence support angiogenesis as a genuine feature of ACC, and this has motivated trials of VEGF/VEGFR inhibitors, multikinase inhibitors, and related vascular strategies.¹²⁴

Even so, results have been uneven. Prospective and retrospective data for agents such as axitinib and sorafenib suggest that single-agent antiangiogenic therapy usually yields modest disease control and rarely durable responses in unselected advanced ACC.⁵² Isolated reports of prolonged benefit, including with sunitinib, indicate that some tumors may be sensitive, but these exceptional responses do not overturn the broader pattern of heterogeneous and generally limited activity.⁷

The antiangiogenic literature also extends beyond classic VEGFR blockade. Early vascular-disrupting therapy, Ang2/Tie2 inhibition, and antiangiogenic combinations with mTOR-directed agents have all shown occasional signals, but mainly in phase 1 basket settings or single-case observations.¹³¹¹⁶ These findings are useful as proof that tumor-vascular biology may be therapeutically relevant, but they are not reliable enough to define standard care. Clinically, they support continued trial development rather than routine off-label use.

Mechanistic and comparative evidence further broadens the angiogenesis framework but remains indirect. Preclinical sorafenib work, post-transcriptional VEGF regulation studies, veterinary biomarker analyses, and comparative oncology treatment series all point toward biologically active vascular programs, yet none establish a predictive human ACC biomarker or a consistently effective antiangiogenic regimen.¹⁴²⁸¹²

FGFR, cMET, and Smaller RTK Niches

Beyond the more extensively studied IGF and VEGF programs, ACC may contain smaller molecular subsets involving FGFR or cMET signaling. Available evidence suggests that these are niche rather than universal targets, with occasional copy-number or expression abnormalities but limited clinical validation.¹⁰⁹

This is an area where the main reliable conclusion is conceptual rather than therapeutic: ACC likely contains biologically distinct subgroups that may not be captured by broad unselected trials. At the same time, current evidence is too sparse to support routine treatment decisions based on these pathways alone. The practical implication is that FGFR and MET findings are most relevant to translational profiling and biomarker-enriched trial design.¹⁰⁹ Older indirect or non-ACC observations provide historical context for this interest but do not materially strengthen the clinical case.¹⁵

Limitations and Pitfalls

The major limitation of this literature is evidentiary fragility. Much of the field depends on retrospective analyses, small ACC cohorts embedded within basket studies, preclinical models, and case reports, all of which limit certainty about treatment effect and generalizability.³⁶⁷

A second limitation is pharmacologic confounding, especially from mitotane. Because mitotane may alter drug metabolism and exposure, negative kinase-inhibitor studies may reflect not only biological resistance but also unfavorable pharmacokinetics. The practical implication is that future ACC trials involving growth-factor inhibitors need explicit attention to mitotane status, exposure timing, and drug-drug interactions.⁵⁷

Finally, growth-factor biology does not encompass all plausible therapeutic vulnerabilities in ACC. Preclinical work on non-RTK targets such as TOP2A underscores that actionable biology may also lie outside classic receptor and angiogenesis frameworks.¹⁶

Role in Management and Research

In current ACC management, growth-factor-directed therapies remain investigational or selectively considered in advanced disease, generally after or alongside more established systemic approaches rather than in place of surgery, standard cytotoxic therapy, or broader multidisciplinary care.¹ Their main present value lies in research: defining molecular subsets, clarifying resistance pathways, and testing rational combinations that may outperform historical single-agent designs.¹¹⁴

Overall, the literature suggests that growth-factor targeting in ACC may produce benefit in a minority of patients, but the average effect in unselected populations has been modest. What is most reliable is not the superiority of any single pathway inhibitor, but the broader lesson that future progress will likely depend on biomarker enrichment, combination strategies, and tighter integration of pharmacology with tumor biology.³⁵⁹

Included Articles

• PMID 19801654: This study is not an ACC trial, but it cites prior primary adrenocortical-cell work showing that TIS11B can destabilize VEGF mRNA and adds a hypoxia-linked post-transcriptional mechanism for VEGF regulation in cancer. It therefore modestly extends the angiogenesis framework by highlighting RNA-stability control as a possible contributor to VEGF variability relevant to ACC biology.¹⁴

• PMID 24423320: PMID 24423320: A phase 2 trial found that axitinib had limited effectiveness as single-agent therapy in advanced ACC, reinforcing the uneven clinical results seen across VEGF/VEGFR-directed approaches. The study supports the note’s current framing that angiogenesis is a real ACC program, but durable benefit from unselected antiangiogenic therapy has generally been modest.⁵

• PMID 31141856: PMID 31141856: A case report in metastatic ACC described sorafenib toxicity that clinically resembled DRESS syndrome but lacked eosinophilia and resolved after drug discontinuation. It extends the note’s angiogenesis/multikinase section by adding a caution about severe early toxicity interpretation rather than efficacy.¹⁷

• PMID 39973216: PMID 39973216: A retrospective veterinary study of toceranib in dogs with high-risk adrenal tumors reported possible clinical benefit and acceptable tolerability, including prolonged disease-free intervals in a small ACC subgroup. Its relevance to human ACC is indirect, but it adds a comparative-oncology signal consistent with ongoing interest in VEGFR-directed multikinase therapy for adrenal malignancies.⁸

• PMID 40215366: A case report described partial regression and progression-free survival of more than 1 year with second-line sunitinib in advanced recurrent ACC, with no severe reported toxicity. It extends the VEGFR/multikinase section by highlighting an exceptional response that does not overturn the broader negative-to-modest trial experience.⁷

• PMID 41276439: A published corrigendum corrected the title of a 2025 ACC study on FGF/FGFR inhibitors, without changing the substantive scientific message. It indirectly supports the existing FGFR section as a citation-level confirmation rather than a new mechanistic or clinical advance.⁹

• PMID 12807934: A phase 1 trial of combretastatin A4 phosphate, a vascular-disrupting agent, reported improvement in liver metastases in one patient with ACC. This extends the note’s angiogenesis framework by adding an early, indirect example of tumor-blood-flow targeting outside conventional VEGFR inhibition, while remaining far too limited to change clinical interpretation.¹³

• PMID 23982248: A phase 1 basket study of lenalidomide plus temsirolimus reported stable disease of at least 6 months in 1 of 3 patients with ACC. This modest, non-ACC-specific signal extends the note’s angiogenesis framework by pointing to antiangiogenic/mTOR combination therapy rather than VEGFR inhibition alone.¹¹

• PMID 26490310: A phase 1 solid-tumor trial of nesvacumab, an anti-Ang2 antibody targeting the Tie2 angiogenesis pathway, reported one partial response of 24 weeks in a patient with ACC. This extends the note’s angiogenesis section beyond VEGF/VEGFR-focused agents while remaining preliminary, non-ACC-specific, and biomarker-unresolved.⁶

• PMID 8267056: A 1993 ovarian cancer study found co-expression of basic FGF and its receptor and suggested an autocrine growth mechanism, with tumor-extract activity measured in bovine adrenocortical endothelial cells. Its relevance to ACC is indirect, but it adds historical context for why FGF-family signaling has been explored in adrenal malignancy.¹⁵

• PMID 23198184: A 2012 case-based review of targeted therapy in ACC summarized EGFR, VEGF, IGF1R, and mTOR rationale and described only brief disease control with erlotinib or sunitinib in two refractory cases, supporting the broader view that early targeted-agent activity in unselected ACC was limited and transient.¹

• PMID 23533247: Preclinical study showing TOP2A overexpression in ACC, functional effects of TOP2A knockdown, and in vitro sensitivity to several TOP2A inhibitors, with aclarubicin the most active compound. This extends the note by highlighting a non-growth-factor therapeutic vulnerability relevant to broader targeted-therapy interpretation, but without clinical ACC validation.¹⁶

• PMID 23956055: A pediatric/young-adult phase 2 basket trial of cixutumumab included a small ACC cohort with no objective responses and one case of temporary stable disease, reinforcing the view that IGF1R blockade in ACC is usually cytostatic at best. The study also showed mild overall toxicity and expected serum IGF-1/IGFBP-3 changes, supporting pathway engagement without establishing reliable clinical benefit.³

• PMID 25087088: A retrospective phase I genitourinary series reported MET amplification in 2 of 12 ACC cases, indicating that MET copy-number gain can occur in a minority of ACCs. However, no objective responses were seen in MET-abnormal tumors on c-MET inhibitor protocols, reinforcing the view that MET remains a preliminary, nonvalidated enrichment marker rather than a proven treatment selector in ACC.¹⁰

• PMID 34108938: A 2021 preclinical study found that sorafenib induced apoptosis in H295R ACC cells and disrupted VEGFR2-associated junctional signaling in monolayer and 3D spheroid models, but also left a surviving subpopulation with features the authors considered concerning for persistent malignancy. It therefore extends the sorafenib literature mechanistically while remaining consistent with the broader view that preclinical activity has not translated into reliable clinical benefit in ACC.²

• PMID 35370210: A veterinary observational study found higher serum VEGF-A concentrations in dogs with adrenal tumors, including adrenocortical carcinoma, than in healthy controls, but values overlapped with benign adrenal lesions and pheochromocytoma. This provides indirect comparative support for angiogenesis in ACC while not informing human treatment efficacy or biomarker specificity.¹²

• PMID 37508400: A 2023 pan-cancer multi-omics prioritization study identified adrenocortical carcinoma among the cancers most plausibly suited for PGF/PlGF-directed therapy, based on integrated expression, survival, and immune-infiltration analyses. For ACC, this is best interpreted as exploratory support for a broader angiogenesis-targeting framework rather than evidence of validated clinical activity.⁴

References

Footnotes

1. Is there a role of targeted agents in the management of adrenocortical cancers?. Case Rep Endocrinol. 2012. PMID: 23198184. Local full text: 23198184.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹

2. Effects of Sorafenib, a Tyrosin Kinase Inhibitor, on Adrenocortical Cancer.. Front Endocrinol (Lausanne). 2021. PMID: 34108938. Local full text: 34108938.md ↩ ↩² ↩³ ↩⁴ ↩⁵

3. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children’s Oncology Group.. Pediatr Blood Cancer. 2014. PMID: 23956055. Local full text: 23956055.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹

4. Comprehensive Analysis for Anti-Cancer Target-Indication Prioritization of Placental Growth Factor Inhibitor (PGF) by Use of Omics and Patient Survival Data.. Biology (Basel). 2023. PMID: 37508400. Local full text: 37508400.md ↩ ↩² ↩³ ↩⁴

5. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer.. J Clin Endocrinol Metab. 2014. PMID: 24423320. Local full text: 24423320.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

6. A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti-Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors.. Clin Cancer Res. 2016. PMID: 26490310. Local full text: 26490310.md ↩ ↩² ↩³ ↩⁴

7. Long-Term Progression-Free Survival With Sunitinib in Advanced Recurrent Adrenocortical Carcinoma.. Am J Ther. Unknown year. PMID: 40215366. Local full text: 40215366.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

8. Toceranib phosphate for the treatment of dogs with high-risk adrenal gland tumours: 16 cases (2019-2023).. J Small Anim Pract. 2025. PMID: 39973216. Local full text: 39973216.md ↩ ↩² ↩³

9. Corrigendum to “FGF/FGFR inhibitors downmodulate c-Myc oncoprotein and hamper the growth of adrenocortical carcinoma” [Biomed. Pharmacother. 192 (2025) 118677].. Biomed Pharmacother. 2025. PMID: 41276439. Local full text: 41276439.md ↩ ↩² ↩³ ↩⁴ ↩⁵

10. MET abnormalities in patients with genitourinary malignancies and outcomes with c-MET inhibitors.. Clin Genitourin Cancer. 2015. PMID: 25087088. Local full text: 25087088.md ↩ ↩² ↩³ ↩⁴

11. Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer.. Invest New Drugs. 2013. PMID: 23982248. Local full text: 23982248.md ↩ ↩² ↩³ ↩⁴

12. Serum vascular endothelial growth factor in dogs with various proliferative diseases.. J Vet Med Sci. 2022. PMID: 35370210. Local full text: 35370210.md ↩ ↩² ↩³

13. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results.. J Clin Oncol. 2003. PMID: 12807934. Local full text: 12807934.md ↩ ↩²

14. Von Hippel-Lindau gene product modulates TIS11B expression in renal cell carcinoma: impact on vascular endothelial growth factor expression in hypoxia.. J Biol Chem. 2009. PMID: 19801654. Local full text: 19801654.md ↩ ↩²

15. Basic fibroblast growth factor and its receptor messenger ribonucleic acids are expressed in human ovarian epithelial neoplasms.. Am J Obstet Gynecol. 1993. PMID: 8267056. Local full text: 8267056.md ↩ ↩²

16. TOP2A is overexpressed and is a therapeutic target for adrenocortical carcinoma.. Endocr Relat Cancer. 2013. PMID: 23533247. Local full text: 23533247.md ↩ ↩²

17. Sorafenib Toxicity Mimicking Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome.. J Drugs Dermatol. 2019. PMID: 31141856. Local full text: 31141856.md ↩