The unraveling of the major initiating mechanisms for AVM formation has propelled the field to think of targeted molecular therapies (Figure 4) that could be used alone or as pre-, peri-, and postinterventional procedures.

Illustration of the main pathways involved in AVMs and their functions in vascular development and maintenance. Selected inhibitors of these pathways are shown in magenta boxes. Red triangles indicate hyperactivating (gain of function) somatic mutations, as seen in nonsyndromic sporadic AVMs. Yellow hexagons indicate loss-of-function mutations responsible for syndromic hereditary AVMs. SMAD, fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic; RIT1, Ras like without CAAX 1.

Targeting the VEGF pathway. Given the pivotal role of VEGF in AVM development, targeting VEGF signaling emerges as a compelling strategy to manage AVMs. Bevacizumab, a monoclonal human anti-VEGF antibody, has demonstrated efficacy in reducing the proliferation of vascular cells, vessel density, and dysplasia index in mice with ALK1-induced brain AVMs (35). However, the results of clinical case reports of bevacizumab efficacy on AVMs have been unsatisfactory. In a single-arm pilot study, two patients with large, deemed unresectable brain AVMs received bevacizumab (5 mg/kg every 2 weeks for 12 weeks) without any significant change in AVM volume (59–61).

An ongoing phase II–III, placebo controlled, clinical trial is evaluating the efficacy and safety of intravenous bevacizumab in patients with symptomatic cerebral AVMs (BevacizuMAV; ClinicalTrials.gov NCT06264531). Although small tyrosine kinase inhibitors targeting the VEGF receptor (VEGFR) are currently being evaluated for HHT, no trial to date has assessed their efficacy in sporadic extracranial AVMs. Bevacizumab has demonstrated more significant efficacy in treating HHT, as shown in various clinical trials. This effectiveness was first observed anecdotally in HHT patients receiving bevacizumab for cancer treatment, during which their HHT symptoms unexpectedly improved (62, 63).

Immunomodulatory imide drugs. Thalidomide exhibits potent antiangiogenic effects by various mechanisms inhibiting cytokines like FGF and VEGF, as well as capillary microvessel formation and EC migration. Thalidomide, by binding to cereblon, a E3 ligase adapter, recognizes some proteins such as VEGF, and facilitates their degradation through the ubiquitin/proteasome pathway (64). Furthermore, thalidomide has been shown to reduce the protein expression of angiopoietin-2 (ANGPT-2) and VEGF as well as to decrease mRNA expression of ANGPT-2 in patients with Crohn’s disease, a condition characterized by elevated levels of these proteins. Through this mechanism, thalidomide significantly inhibited cell proliferation, cell migration, and capillary-like tube formation in human umbilical vein ECs (HUVECs). These findings may explain the antiangiogenic efficacy of thalidomide (65).

Thalidomide has strong antiinflammatory and immunomodulatory properties by targeting TNF-α and nitric oxide. In a mouse model of brain AVM, thalidomide and its derivative lenalidomide reduced dysplastic vessels and hemorrhage while increasing mural cell coverage, possibly through increased PDGF-β expression. These effects were accompanied by a reduction in CD68+ cells and inflammatory cytokines in murine cerebral AVM lesions (66). Building upon these findings, a prospective clinical study was conducted evaluating thalidomide in 18 patients with extensive, recurrent, and highly symptomatic extracranial AVMs refractory to conventional treatments (67). An initial dose of 50 mg thalidomide daily was escalated to 100 or 200 mg daily within two weeks for the first five patients. Subsequent patients received a continuous lower dose of 50 mg daily due to grade 3 adverse events (asthenia, erythroderma, and small cerebral infarct) observed in four of the patients receiving the higher dose. Thalidomide led to significant clinical improvement in all patients, including pain reduction, cessation of bleeding, and healing of ulcerations. Cardiac overload that was present in three patients resolved. Notably, thalidomide induced angiographic reduction in two patients and disappearance of AVMs in another one, with sustained effects even after discontinuation. In a similar way, thalidomide was shown to reduce the severity and frequency of epistaxis in patients with HHT, increasing the levels of hemoglobin. In vivo studies showed that thalidomide treatment was able, through increased PDGF-B expression in ECs, to stimulate mural cell coverage (68). Recently, pomalidomide demonstrated a superior efficacy compared to placebo in patients with HHT in significantly reducing epistaxis severity (69).

Thalidomide may also be promising in association with or following embolization and/or surgery. In this study, thalidomide was associated with embolization in seven patients (two from the high-dose and five from the low-dose group). Compared with the previous history and efficacy of embolization alone on these patients’ lesions, the association of embolization with thalidomide allowed a more efficient and durable efficacy. Embolization can, by denudation of the vessel wall surface, trigger hypoxia-inducible transcription factor (HIF) signaling and subsequently stimulate angiogenesis by release of VEGF, which also enhances the intrinsically high cytokine activity in the AVM, causing an increase in the level of inflammation (45). Thalidomide, by targeting angiogenic pathways as well as the inflammatory reaction, may potentialize the effect of embolization compared with embolization alone.

Thalidomide is generally well tolerated, with manageable toxicity. The most common side effects were mild fatigue and polyneuropathy, which resolved upon discontinuation of the medication. While thalidomide has been associated with an increased risk of thrombotic venous events in cancer patients, this risk does not seem to be significantly elevated in vascular anomaly patients, as seen in this study and shown in an HHT series. Nonetheless, caution is warranted, as one case of fatal nose bleeding occurred in an HHT patient receiving thalidomide, indicating a potential risk of vessel wall destabilization and increased bleeding risk (70, 71). Thalidomide derivatives appear as promising alternative agents due to their better toxicity profile. A large metaanalysis comparing thalidomide and lenalidomide in myeloma reported that the discontinuation rate from thalidomide trials was higher than that from lenalidomide trials, due to the toxicity profiles (72).

Targeting the PI3K/AKT/mTOR pathway. Given the interplay between the RAS and PI3K pathways, mTOR inhibitors have also been trialed. Some clinical benefits have been observed, but significant responses have not been consistent (23, 73). In a retrospective analysis, the efficacy of sirolimus was assessed in ten patients with extracranial AVMs, including seven children (73). The administered sirolimus doses ranged from 0.6 to 3.5 mg/m2, with a median treatment duration of 24.5 months (ranging from 4.5 to 35 months). Among the patients, five exhibited no response to sirolimus treatment, while the remaining five showed a partial response, observed at a median time of three months (interquartile range [IQR]: 1; 5), reflecting a limited efficacy of sirolimus in the management of extracranial AVMs. In another retrospective trial including four patients with AVM, sirolimus was not efficient (74). Considering the specific vascular pathways involved, mTOR inhibitors may be best suited for PTEN-mutated AVMs. Some case reports or series including PTEN-related AVMs showed improvement in symptoms of vascular anomalies, induced by sirolimus (75–78). However, further research is needed to confirm this.

Targeting the MAPK pathway. As previously discussed, the MAPK pathway is frequently dysregulated in AVMs. Preclinical investigations have demonstrated that the MEK inhibitor trametinib can enhance survival and normalize vessel morphology in mice with the KRAS mutation (6). Trametinib is an oral, reversible, and highly selective MEK1/2 inhibitor. Two clinical cases demonstrated the potential efficacy of trametinib in treating AVMs. A KRAS-positive AVM of the chest and spinal cord was treated with trametinib for up to 2.5 years with a subsequent reduction in size and in lesional blood flow rate (79). Moreover, a 16-year-old girl with CM-AVM2 and EPHB4 mutation was successfully managed using trametinib (80). This patient presented with multiple Bier spots, painful limb overgrowth, and heart failure. Although trametinib was initiated at 2 mg daily, it was swiftly reduced due to skin toxicity, a well-known related adverse event. Despite the lower dose of 0.5 mg daily, cardiac function improved, and leg pain decreased without diminishing hypertrophy.

At the ISSVA World Congress 2022, we unveiled preliminary findings from our TRAMAV clinical trial, a prospective single-center study (EudraCT: 2019-003573-26) (81). Trametinib showed promising efficacy in the ten patients with extracranial AVMs. However, acneiform rash became a notable concern, particularly in the first two patients who began treatment with a daily dose of 2 mg and developed grade 3 skin toxicity, prompting us to adjust the dosage. Trametinib resulted in significant symptom improvement in eight patients, alleviating bleeding, pain, and ulceration. The second part of the TRAMAV trial will focus on evaluating trametinib in children, where skin toxicity may be less pronounced owing to their prepubertal status, thus shedding further light on its therapeutic potential in this population. Other MEK1/2 inhibitors have been approved by the FDA for oncologic indications, including binimetinib and selumetinib, and they may also be active in AVMs. Cobimetinib is currently being evaluated in a phase II trial enrolling patients with extracranial AVM (COBI-AVM study; NCT05125471). None of the molecules discussed here are currently approved for AVMs, underlying the important need to develop medical management for vascular anomalies.

Finding the right dose. Interestingly, the doses of targeted agents like bevacizumab, thalidomide, and trametinib required to effectively treat AVMs are notably lower than those used in cancer therapy. As lesion disappearance or strong size reduction has rarely been seen in vascular anomaly patients treated with medications, the goal now rather is to reach the maximal reduction in signs and symptoms with the smallest possible dose to reduce side effects. By precisely targeting these driver cascades at lower doses, treatment remains effective while reducing toxicity, allowing for longer treatment durations with fewer side effects.

Finding the right drug. AVMs and certain cancers share hyperactivated molecular pathways, occasionally involving identical hotspot mutations. This overlap opens the door for the repurposing of oncologic drugs to treat AVMs. Many cancer treatments targeting these dysregulated pathways are well characterized, and we reviewed some that have already been explored in the context of AVM management. Advances in the understanding of AVM pathophysiology, supported by in vitro studies, animal models, and genetic testing, combined with knowledge of side effect profiles from cancer therapies facilitate the faster transition of these agents into clinical trials for AVM patients. Unlike cancer, AVMs represent chronic conditions, meaning that any pharmacologic therapy, unless curative, would require prolonged administration. This extended use increases the likelihood of cumulative toxicity or the exacerbation of side effects, presenting a challenge for long-term tolerability. Therefore, the future of AVM treatment may lie in a multimodal approach, integrating drug therapies with ablative techniques, such as embolization or surgical resection, mirroring the combinatory strategies often employed in cancer management. Moreover, novel tools such as vascular organoids that would express one of the AVM-associated pathogenic variants, e.g., the frequent hot-spot changed in KRAS, could be used as models for high-throughput screens, at least for the already FDA-approved drugs (82).