Abstract
Current anti-angiogenic therapies using vascular endothelial growth factor-A/vascular endothelial growth factor receptor-2 (VEGF-A/VEGFR2) inhibitors lack dynamic biomarkers that can facilitate patient selection and optimize dosing; this can lead to suboptimal and unsatisfactory outcomes and significant toxicities. To address this, we propose a paradigm shift leveraging the dopamine D2 receptor (DRD2)/VEGF-A paracrine feedback loop. In the tumor microenvironment, VEGF-A selectively induces endothelial DRD2 expression through specific transcriptional mechanisms – a molecular signature that is absent in quiescent normal vasculature. DRD2 activation serves as a potent, tumor-specific vascular brake on VEGFR2 phosphorylation and paracellular permeability. By utilizing FDA-approved DRD2 agonists as functional probes, clinicians can implement a dopaminergic challenge to identify windows of maximal VEGF-dependency via dynamic imaging. This approach transforms anti-angiogenic interventions from empirical into a precision theranostic platform, enabling real-time assessment of tumor VEGF-dependency and rational treatment selection that maximizes efficacy while minimizing toxicity.
Introduction
Although the era of anti-vascular endothelial growth factor (VEGF) therapy is two decades old, its clinical practice continues to rely on empirical dosing (, ) despite VEGF-A dependency fluctuating as tumors evolve or activate alternative escape pathways (, ). There remains a lack of a functional probe that can identify these transient windows of tumor vulnerability (, ). Consequently, patients often receive prolonged, nonselective blockading agents that lead to the anti-angiogenic paradox: excessive vascular pruning that induces hypoxia, promotes therapy resistance, and incurs systemic toxicities such as hypertension and thromboembolism (, ).
A biologically tuned feedback system
Emerging evidence suggests that the tumor microenvironment harbors intrinsic regulatory mechanisms that are amenable to therapeutic exploitation. Among these, the dopamine D2 receptor (DRD2)–VEGF-A axis functions as a biological rheostat of angiogenesis (). Consistent with this phenomenon, clinical studies of patients with giant pituitary tumors, a non-malignant tumor, have revealed that cabergoline, a potent ergot-derived DRD2 agonist, can suppress tumor growth through the inhibition of pathological angiogenesis and subsequent cellular proliferation (). Unlike tyrosine kinase inhibitors, which indiscriminately attenuate systemic signaling (), cabergoline and other DRD2 agonists such as quinagolide exert context-dependent inhibition (–). This mechanism preserves homeostatic vascular integrity while selectively targeting the aberrant tumor endothelium, thereby offering a superior therapeutic index as well as a promising avenue for precision modulation of the tumor microenvironment.
Mechanistically, VEGF-A activates the transcription factor KLF11 via the ERK1/2 pathway, which, in turn, upregulates DRD2 specifically in tumor endothelial cells. This establishes a self-regulating feedback loop where high VEGF-A levels prime the endothelium for DRD2-mediated suppression. Upon activation, DRD2 inhibits VEGF-A-induced phosphorylation of the tight junction protein ZO-1 as well as vascular endothelial-cadherin/catenin complexes at the adherens junction, thus preserving endothelial adhesion and restricting paracellular permeability (). Additionally, DRD2 signaling promotes vascular maturation by upregulating endothelial KLF2 and stimulating pericyte-derived Ang-1 expression, thereby facilitating mural cell recruitment and vessel normalization to stabilize the endothelium against VEGF-A-driven remodeling ().
Quiescent normal vessels express minimal or no DRD2 in the absence of sustained VEGF-A stimulation (). This intrinsic biological phenomenon confers tumor-endothelial selectivity not achieved by nonselective anti-VEGF-A/VEGFR2 antibodies or tyrosine kinase inhibitors that can induce deleterious vascular pruning, intratumoral hypoxia, and systemic toxicity. Consequently, the VEGF-A–ERK1/2–KLF11 signaling axis emerges as a robust endothelial biomarker for predicting DRD2-agonist responsiveness; however, this insight warrants high-resolution spatial transcriptomic mapping to enable precision stratification across diverse tumor microenvironments.
Lessons from vascular homeostasis
While classically recognized as a central neurotransmitter synthesized in the specialized neurons of the brain, dopamine is also substantially produced in mesenteric organs where it exerts pivotal peripheral effects (). Beyond its established role in motor control, dopamine functions as a systemic homeostatic regulator that modulates cardiovascular, renal, and endocrine functions through the dynamic interplay of D1- and D2-like receptor signaling (). Emerging preclinical evidence suggests that endothelial DRD2 activation suppresses VEGF-A-induced angiogenesis and vascular permeability in the tumor microenvironment by inhibiting VEGFR-2 phosphorylation and downstream MAPK/focal adhesion kinase signaling. Given the well-characterized safety profile of FDA-approved DRD2 agonists (e.g., cabergoline) (–, ), this signaling axis positions endothelial DRD2 as a highly tractable therapeutic target for selectively attenuating VEGF-A-driven vascular dysfunction.
In non-oncologic clinical conditions involving pathological VEGF-A-driven vascular leak, such as ovarian hyperstimulation syndrome (OHSS), neovascular endometriosis, and sepsis-related lung injury, DRD2 agonists or dopamine acting through D2 receptors effectively mitigate edema and ascites (, , ). Crucially, these agents normalize vascular permeability without the systemic pressor effects or proteinuria that are characteristic of VEGF-A blockade (). This suggests that DRD2 activation facilitates vascular normalization rather than deprivation, thereby preserving the integrity of the vessel wall while quenching pathological signaling (–, ).
The dopaminergic challenge: a theranostic protocol
We propose exploiting this unique biology for a functional diagnostic protocol: the “Dopaminergic Challenge.” Because endothelial DRD2 expression is a proximal downstream consequence of VEGF-A activity (), the acute vascular response to a DRD2 agonist serves as a live, physiological sensor of the tumor’s angiogenic drive. In this clinical workflow, a baseline assessment of vascular permeability is established via dynamic contrast-enhanced MRI to determine the volume transfer constant (Ktrans) (). Following the oral administration of cabergoline using the dosing regimen that was previously shown to inhibit VEGF-A-induced vascular permeability in patients with OHSS (0.5 mg daily for 8 days) (), the MRI will be performed again. A >40% reduction in the Ktrans would indicate a highly active, VEGF-A-dependent state, establishing a high probability of the existence of an “optimal window” for standard VEGF-A inhibitor administration (). Conversely, the lack of a response would indicate that the tumor transitioned to VEGF-A-independent escape pathways, thereby rendering alternative therapeutic modalities more prudent and sparing the patient any adverse effects of continued (and futile) VEGF-A blockade therapy (Figure 1). Importantly, the ergot DRD2 agonist cabergoline-treated patients do not show cardiac valvular defects at durations and doses used to inhibit VEGF-A-induced angiogenesis and vascular permeability in OHSS and endometriosis ().
Figure 1
The translational roadmap
Validating this approach requires a multidimensional strategy that bridges molecular mapping with adaptive clinical trial design. Initial efforts must focus on high-resolution spatial transcriptomics and multiplex immunofluorescence to quantify the dopaminergic window (i.e., the DRD2-responsive VEGF-A window) and identify the precise histological tumor types and stages of progression where DRD2 expression is most prominent. Concurrently, preclinical studies are needed to confirm the correlation between DRD2-induced reductions in Ktrans and VEGF-A activity. A logical next step would be to initiate pilot “go/no-go” trials () wherein the response to the dopaminergic challenge dictates the administration of VEGF-A inhibitors. This approach will determine whether receptor-mediated feedback can accurately predict the therapeutic index of anti-angiogenic agents, ultimately transforming them from blunt instruments of deprivation into precision tools for vascular synchronization.
Conclusion
Repurposing DRD2 agonists shifts the focus of anti-angiogenesis therapy from deprivation to synchronization. By engaging an endogenous feedback loop, we can sense the tumor’s requirements in real time and steer the vasculature toward a normalized state. This biologically resonant approach offers a pathway to anti-angiogenic therapy that is adaptive, selective, and functionally informed. However, clinical implementation of this theranostic strategy will require the prospective validation of DRD2 expression as a biomarker, standardization of dynamic contrast-enhanced-MRI protocols to ensure reproducible Ktrans measurements, and assessment of pharmacologic safety and feasibility in diverse oncological patient populations. The operational challenges of integrating functional imaging into adaptive trial designs and routine practice must also be addressed prior to broader adoption.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author contributions
MS: Data curation, Formal analysis, Validation, Writing – original draft, Writing – review & editing. VA: Data curation, Formal analysis, Validation, Writing – original draft, Writing – review & editing. PD: Validation, Writing – review & editing. SB: Validation, Writing – original draft, Writing – review & editing, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Supervision.
Funding
The author(s) declared that financial support was received for this work and/or its publication. MR Sahu, V Akkanapally, and S Basu were supported by the Ohio State University Comprehensive Cancer Center fund to Sujit Basu.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Correction note
A correction has been made to this article. Details can be found at: 10.3389/fonc.2026.1978685.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
DudaDGBatchelorTTWillettCGJainRK. VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med. (2007) 13:223–30. doi: 10.1016/j.molmed.2007.04.001
2
CaoYLangerRFerraraN. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov. (2023) 22:476–95. doi: 10.1038/s41573-023-00671-z
3
SenninoBMcDonaldDM. Controlling escape from angiogenesis inhibitors. Nat Rev Cancer. (2012) 12:699–709. doi: 10.1038/nrc3366
4
ShiZKuaiMLiBAkowuahCFWangZPanYet al. The role of VEGF in cancer angiogenesis and tumorigenesis: insights for anti-VEGF therapy. Cytokine. (2025) 189:156908. doi: 10.1016/j.cyto.2025.156908
5
JainRKDudaDGWillettCGSahaniDVZhuAXLoefflerJSet al. Biomarkers of response and resistance to anti-angiogenic therapy. Nat Rev Clin Oncol. (2009) 6:327–38. doi: 10.1038/nrclinonc.2009.63
6
CantelmoARPircherAKaluckaJCarmelietP. Vessel pruning or healing: endothelial metabolism as a novel target? Expert Opin Ther Targets. (2017) 21:239–47. doi: 10.1080/14728222.2017.1282465
7
SantorsolaMCapuozzoMNastiGSabbatinoFDiMADiMGet al. Exploring the spectrum of VEGF inhibitors' toxicities from systemic to intra-vitreal usage in medical practice. Cancers (Basel). (2024) 16:350. doi: 10.3390/cancers16020350
8
SarkarCChakrobortyDGoswamiSFanHMoXBasuS. VEGF-A controls the expression of its regulator of angiogenic functions, dopamine D2 receptor, on endothelial cells. J Cell Sci. (2022) 135:jcs259617. doi: 10.1242/jcs.259617
9
Astaf'evaLShishkinaLKalininPKadashevBMelnichenkoGTserkovnayDet al. Decrease of proliferative potential and vascular density of giant prolactinoma in patients treated with cabergoline. Asian J Neurosurg. (2020) 15:385–90. doi: 10.4103/ajns.AJNS_16_20
10
Shyam SunderSSharmaUCPokharelS. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct Target Ther. (2023) 8:262. doi: 10.1038/s41392-023-01469-6
11
PellicerNGallianoDPellicerA. Ovarian hyperstimulation syndrome. In: LeungPCKAdashiEY, editors.The ovary. Academic Press, MA (2019). p. 346–61.
12
DiVastaADStamoulisCGallagherJSLauferMRAnchanRHornsteinMD. Nonhormonal therapy for endometriosis: a randomized, placebo-controlled, pilot study of cabergoline versus norethindrone acetate. F S Rep. (2021) 2:454–61. doi: 10.1016/j.xfre.2021.07.003
13
MathisTBaudinFMarietASAugustinSBricoutMPrzegralekLet al. DRD2 activation inhibits choroidal neovascularization in patients with Parkinson's disease and age-related macular degeneration. J Clin Invest. (2024) 134:e174199. doi: 10.1172/JCI174199
14
BhattacharyaRSinhaSYangSPPatraCDuttaSWangEet al. The neurotransmitter dopamine modulates vascular permeability in the endothelium. J Mol Signal. (2008) 3:14. doi: 10.1186/1750-2187-3-14
15
ChakrobortyDSarkarCYuHWangJLiuZDasguptaPSet al. Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Kruppel-like factor-2 expression in tumor endothelial cells. Proc Natl Acad Sci USA. (2011) 108:20730–5. doi: 10.1073/pnas.1108696108
16
EisenhoferGAnemanAFribergPHooperDFåndriksLLonrothHet al. Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab. (1997) 82:3864–71. doi: 10.1210/jcem.82.11.4339
17
MissaleCNashSRRobinsonSWJaberMCaronMG. Dopamine receptors: from structure to function. Physiol Rev. (1998) 78:189–225. doi: 10.1152/physrev.1998.78.1.189
18
AgarwalSSrivastavaVKArshadZSharmaPPrakashR. Effect of dopamine as a vascular endothelial growth factor antagonist on the development of acute lung injury in sepsis patients. Cureus. (2024) 16:e64102. doi: 10.7759/cureus.64102
19
O'ConnorJPJacksonAParkerGJJaysonGC. DCE-MRI biomarkers in the clinical evaluation of anti-angiogenic and vascular disrupting agents. Br J Cancer. (2007) 96:189–95. doi: 10.1038/sj.bjc.6603515
20
AlvarezCMartí-BonmatíLNovella-MaestreESanzRGómezRFernández-SánchezM. Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. J Clin Endocrinol Metab. (2007) 92:2931–7. doi: 10.1210/jc.2007-0409
21
StilesCETetteh-WayoeETBestwickJSteedsRPDrakeWM. A meta-analysis of the prevalence of cardiac valvulopathy in hyperprolactinemic patients treated with cabergoline. J Clin Endocrinol Metab. (2019) 104:523–38. doi: 10.1210/jc.2018-01071
22
Chuang-SteinCKirbySFrenchJKowalskiKMarshallSSmithMKet al. A quantitative approach for making go/no-go decisions in drug development. Ther Innov Regul Sci. (2011) 45:187–202. doi: 10.1177/009286151104500213
Summary
Keywords
angiogenesis, cancer, dopamine D2 receptor agonists, therapy, vascular endothelial growth factor receptor-2, vascular endothelial growth factor-A
Citation
Sahu MR, Akkanapally V, Dasgupta PS and Basu S (2026) Beyond inhibition: harnessing the DRD2–VEGF-A feedback loop for precision anti-angiogenesis therapy in cancer. Front. Oncol. 16:1818655. doi: 10.3389/fonc.2026.1818655
Received
26 February 2026
Revised
15 April 2026
Accepted
08 May 2026
Published
28 May 2026
Corrected
02 September 2026
Volume
16 - 2026
Edited by
Shaosen Zhang, Chinese Academy of Medical Sciences and Peking Union Medical College, China
Reviewed by
Sk. Kayum Alam, University of Minnesota Twin Cities, United States
Ameya K. P., Saveetha Institute of Medical and Technical Sciences, India
Updates
Copyright
© 2026 Sahu, Akkanapally, Dasgupta and Basu.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sujit Basu, Sujit.Basu@osumc.edu
‡These authors have contributed equally to this work and share first authorship
†Present address: Partha Sarathi Dasgupta, Retired, Kolkata, India
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.