Targeted Therapy Beyond Growth Factors

Targeted Therapy

Adrenocortical carcinoma (ACC) has prompted investigation of targeted treatments that extend beyond classic growth-factor and receptor tyrosine kinase pathways. In this context, non-growth-factor targeted therapy refers to strategies aimed at adrenal-specific metabolic dependencies, cell-cycle and proteostasis programs, lineage-associated cell-surface targets, and platform approaches designed to overcome drug resistance or improve delivery. These approaches sit largely in the translational and early clinical research space rather than in established routine care.¹²

The biologic rationale for this broader targeted-therapy landscape comes from several recurring features of ACC: steroidogenic and lipid-handling specialization, frequent proliferative and chromosomal instability signals, and phenotypic plasticity associated with invasion, metastasis, and treatment resistance.¹³⁴ At the same time, the evidence base remains limited. Much of the literature consists of preclinical studies, small retrospective or early-phase datasets, and occasional case reports, so apparent vulnerabilities may not translate into clinically achievable or durable benefit.⁵⁶⁷

Current data therefore suggest a field defined more by plausible biologic targets than by validated treatment standards. Across themes, single-agent activity has often been modest or inconsistent, while combination strategies and biomarker-guided selection appear more promising in principle than in proven practice.⁵⁶⁸ This has practical implications for ACC management: outside trials, surgery, mitotane-based treatment, cytotoxic therapy, and selected immunotherapy remain the main comparators, and non-growth-factor targeted approaches are best understood as investigational additions rather than replacements.

Diagnostic and Biologic Context

ACC differs from many solid tumors in that adrenal steroidogenesis and cholesterol handling are central to tumor biology, creating target classes that are less relevant in non-endocrine cancers. This helps explain the persistent interest in lipid metabolism, steroidogenic regulation, and membrane-trafficking pathways as potential therapeutic entry points.¹³ The most reliable conclusion is that these pathways are biologically important; what remains uncertain is which of them represent druggable dependencies in patients rather than descriptive tumor features.

A second broad theme is heterogeneity. Molecular pathway activation appears variable across ACCs, and the same target may be linked to proliferation in one subset, hormone secretion in another, and little therapeutic sensitivity in unselected populations.⁶² Clinically, this limits extrapolation from cell lines or isolated biomarker-positive cases and supports a preference for biomarker-enriched trial designs.

Lipid and Steroid Metabolism Targets

Lipid-directed therapy is one of the most ACC-specific targeted concepts because adrenal tumors depend on cholesterol uptake, storage, trafficking, and steroidogenic use. The literature supports a broad vulnerability in lipid homeostasis rather than a single validated drug mechanism, with cholesterol-handling and sphingolipid signaling both implicated.¹³ This is a relatively coherent biologic theme, but its clinical reliability remains limited because direct therapeutic translation has been uneven.

Sphingosine kinase 1 (SphK1) illustrates this pattern. ACC tissue studies and experimental models suggest that SphK1 overexpression may correlate with more advanced disease and may promote proliferation and invasion, while pharmacologic inhibition has shown antitumor effects in vitro and in xenografts.¹ These data support sphingolipid metabolism as a plausible research target, but they do not yet establish a treatment standard or a validated predictive biomarker.

Indirect literature has also expanded the lipid framework by linking cholesterol to transcriptional regulation, including ERRα-associated metabolic programs.³ This conceptual extension may help explain why cholesterol perturbation influences tumor behavior beyond membrane composition or steroid synthesis alone, but the practical implication remains mainly hypothesis generation for combination studies rather than immediate clinical decision-making.

Cell-Cycle, Proteostasis, and Cell-Death Programs

Many ACCs display aggressive proliferative behavior, making cell-cycle and stress-response pathways attractive targets. Available evidence suggests that these programs are biologically relevant, but it is less clear which nodes produce selective and durable therapeutic effects in humans.⁹⁴ In practice, this favors their use as frameworks for subgroup discovery and rational combinations rather than as stand-alone therapies in unselected disease.

mTOR-pathway experience highlights the limitations of pathway-directed monotherapy. Small clinical experience with everolimus in heavily pretreated metastatic ACC showed limited radiographic benefit, and translational data indicate that mTOR activation is heterogeneous and present in only a subset of tumors.⁵⁶ The most reliable inference is therefore negative: mTOR blockade alone is unlikely to be broadly effective in unselected ACC, particularly when mitotane-related pharmacokinetic interactions may further reduce exposure.⁵

Broader proteostasis and ubiquitin-system concepts extend this section but remain even earlier in development. Reviews of deubiquitinases and related regulatory machinery suggest theoretical relevance to endocrine malignancies, including ACC, because these systems intersect with DNA repair, apoptosis, and cell-cycle control.⁹ Similarly, PANoptosis has been proposed as a conceptual framework for integrated tumor cell death, but ACC-specific therapeutic evidence is lacking.⁴ The practical implication is that these areas may help organize future mechanism-based research, but they do not yet define actionable clinical targets.

Cell-Surface, Lineage, and Plasticity-Associated Targets

Cell-surface targeting in ACC has focused on lineage-associated antigens and invasive phenotypes that may be exploited by immunotoxins, antibody-drug conjugates, or other selective delivery platforms. This area is appealing because it may offer a way to target tumor identity rather than only intracellular signaling.²⁷ However, the evidence is mixed, and expression alone is unlikely to guarantee treatment sensitivity.

Among these targets, DLK1 currently appears to have the strongest translational momentum. Although direct ACC clinical data are still limited, surfaceome-based and preclinical studies support DLK1 as a lineage-linked surface antigen with possible relevance to poorly differentiated or treatment-resistant states.² What appears reliable is target prioritization at the discovery level; what remains uncertain is whether expression, payload delivery, and resistance mechanisms can be integrated into a clinically effective strategy.

By contrast, older receptor-ligand observations such as endothelin-1 expression in individual ACC cases are best viewed as exploratory signals rather than established therapeutic avenues.⁷ Their main value is to broaden the map of possible surface biology, but generalizability from single-case observations is weak and should not be overinterpreted.

Platform Strategies, Drug Resistance, and Repurposing

Because ACC is rare and often chemoresistant, some of the non-growth-factor literature is best understood as platform development rather than target validation. These studies examine ways to improve drug retention, alter pharmacology, or repurpose existing agents with multi-pathway effects.⁸¹⁰ The most dependable contribution of this work is methodological: it identifies obstacles to effective therapy and suggests how future combinations might be designed.

Drug-efflux modulation is one example. Cross-tumor work on Ptch1 inhibition supports the idea that blocking efflux mechanisms may increase intracellular retention of cytotoxic agents, reinforcing earlier ACC-related platform concepts without yet proving clinical benefit in ACC itself.⁸ This suggests that resistance biology may be as important as target biology when designing combination regimens.

Repurposing and pharmacology-focused reports add a similar cautionary perspective. Reviews of agents such as mebendazole mainly support low-cost, mechanism-diverse hypothesis generation rather than disease-specific efficacy claims, while older pharmacokinetic observations with suramin illustrate how concomitant medications can materially change exposure to investigational drugs.¹⁰¹¹ Clinically, this means that trial interpretation in ACC requires careful attention to drug-drug interactions, supportive medications, and mitotane-associated metabolic effects.

Limitations and Role in Management

Across categories, the main limitation is the gap between biologic plausibility and demonstrated patient benefit. Retrospective data, preclinical systems, and indirect evidence from other tumor types generate useful hypotheses, but they do not reliably establish comparative efficacy against standard ACC treatments.⁵⁶⁸ As a result, most non-growth-factor targeted approaches remain research tools or trial options rather than routine components of care.

Taken together, the literature suggests that the most promising direction is integrated development: matching target expression or pathway dependence with pharmacokinetics, resistance markers, and rational combination partners from the outset.⁵²¹ For researchers, this framework may be more informative than any single pathway result; for clinicians, it reinforces that investigational targeted therapy beyond growth factors should usually be interpreted in relation to surgery, mitotane-based therapy, cytotoxic regimens, and clinical-trial availability.

Included Articles

• PMID 38106022: A neuroblastoma surfaceome preprint prioritized DLK1 through combined proteomic, transcriptomic, and epigenomic analysis and showed preclinical activity for a DLK1-targeting ADC. Its ACC relevance is indirect, but the paper notes high DLK1 expression in ACC and supports surfaceome-based target discovery as a useful framework for this disease.²

• PMID 15571028: A 2004 case report found strong endothelin-1 immunoreactivity in a cortisol-secreting adrenocortical carcinoma and proposed the endothelin axis as a possible therapeutic target. Its ACC relevance is direct but limited by single-case, non-interventional evidence, so it mainly broadens the list of exploratory receptor-ligand programs.⁷

• PMID 23417626: A 2013 four-patient ACC case series reported that everolimus was well tolerated but showed no clear clinical benefit as salvage therapy in progressive metastatic disease. The authors emphasized possible mitotane-related CYP3A4 drug interactions and compensatory pathway activation as explanations for limited efficacy, making the paper most relevant as a cautionary combination-design and pharmacology note rather than as support for single-agent mTOR inhibition.⁵

• PMID 24891456: This study found heterogeneous mTOR-pathway activation across normal adrenal tissue and adrenocortical tumors, with evidence of pathway activity in only a subset of ACCs. In primary cultures, sirolimus affected cell survival or cortisol secretion only sporadically, reinforcing the limited promise of unselected single-agent mTOR inhibition.⁶

• PMID 9165547: A 1997 pharmacokinetic analysis of suramin found that concomitant furosemide reduced suramin clearance and could increase drug exposure during prolonged treatment. ACC relevance is indirect because only one included patient had adrenocortical carcinoma, but the paper usefully highlights medication-interaction risks in ACC trial pharmacology.¹¹

• PMID 25605410: A 2015 review identifies deubiquitinases as potential cancer targets and notes relevance to endocrine carcinogenesis, including ACC, mainly as a conceptual framework rather than direct ACC treatment evidence. Its main contribution here is to extend stress-response and cell-cycle targeting toward ubiquitin-system regulation while emphasizing target-selectivity challenges.⁹

• PMID 26673009: A 2016 ACC study identified SphK1 overexpression as a marker of more advanced and poorer-prognosis disease and linked it functionally to proliferation, invasion, and survival signaling. Fingolimod (FTY720) showed preclinical antitumor activity, including xenograft inhibition and limited cell-line-specific enhancement with mitotane, suggesting a sphingolipid-metabolism vulnerability distinct from but related to other lipid-targeting strategies in ACC.¹

• PMID 30254608: A 2018 review proposes that cholesterol can function as an endogenous ERRalpha agonist and discusses how this may influence cancer metabolic programs. For ACC, the relevance is indirect but it extends lipid-focused framing by suggesting a transcriptional cholesterol-signaling axis beyond SOAT1 and trafficking biology.³

• PMID 33810240: Melanoma experiments with methiothepin provide cross-tumor confirmation of the Ptch1 drug-efflux platform already noted in ACC literature: Ptch1 inhibition increased doxorubicin retention and improved sensitivity to several therapies, including in resistant cells. Its ACC relevance is therefore supportive and mechanistic rather than directly trial-guiding.⁸

• PMID 36674870: A review of mebendazole repurposing in brain cancer is only indirectly relevant to ACC, but it explicitly includes ACC among cancers under exploratory evaluation and reinforces the broader note theme that approved non-oncology drugs can serve as affordable, mechanism-diverse combination platforms rather than immediately validated ACC therapies.¹⁰

• PMID 38129399: A 2023 review summarizes PANoptosis as a coordinated inflammatory cell-death program integrating pyroptosis, apoptosis, and necroptosis, and notes possible tumor-suppressive relevance in cancers including ACC. For ACC, the evidence presented is conceptual rather than disease-specific, mainly extending stress-response and cell-death framing rather than adding a validated target.⁴

References

Footnotes

1. Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression.. Oncotarget. 2016. PMID: 26673009. Local full text: 26673009.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

2. A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.. bioRxiv. 2024. PMID: 38106022. Local full text: 38106022.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

3. Cholesterol as an Endogenous ERRα Agonist: A New Perspective to Cancer Treatment.. Front Endocrinol (Lausanne). 2018. PMID: 30254608. Local full text: 30254608.md ↩ ↩² ↩³ ↩⁴ ↩⁵

4. Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases.. Cell Death Dis. 2023. PMID: 38129399. Local full text: 38129399.md ↩ ↩² ↩³ ↩⁴

5. Everolimus therapy for progressive adrenocortical cancer.. Endocrine. 2013. PMID: 23417626. Local full text: 23417626.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

6. Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors.. Endocr Relat Cancer. 2014. PMID: 24891456. Local full text: 24891456.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

7. Expression of endothelin-1 by adrenocortical carcinoma: a new target for anti-cancer therapy?. Acta Chir Belg. 2004. PMID: 15571028. Local full text: 15571028.md ↩ ↩² ↩³ ↩⁴

8. Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells.. Molecules. 2021. PMID: 33810240. Local full text: 33810240.md ↩ ↩² ↩³ ↩⁴ ↩⁵

9. Deubiquitinases and the new therapeutic opportunities offered to cancer.. Endocr Relat Cancer. 2015. PMID: 25605410. Local full text: 25605410.md ↩ ↩² ↩³

10. Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers.. Int J Mol Sci. 2023. PMID: 36674870. Local full text: 36674870.md ↩ ↩² ↩³

11. Pharmacometric analysis of the effect of furosemide on suramin pharmacokinetics.. Pharmacotherapy. 1997. PMID: 9165547. Local full text: 9165547.md ↩ ↩²