or systemic antiangiogenic agents has shown limited success.
The hallmark ocular lesion associated with VHL disease
is the retinal capillary hemangioblastoma, present in
about 37% of VHL patients.20 Investigative work, such as
the study by Wong et al,21 used intravitreal ranibizumab
a VEGF trapping agent. In the Wong study,21 five patients
received an average of 10 intravitreal injections over an
average of 47 weeks. Unfortunately, ranibizumab had
minimal beneficial effect on most VHL-associated retinal
hemangioblastomas, although there was possible efficacy
in a patient with the smallest lesion with less exudation.
More promising results were achieved in a second study
in which bevacizumab was used over 60 months in a patient
with progressive visual loss to a VHL-associated macular
and optic nerve hemangioblastoma.22 After undergoing
a treatment regimen of 15 injections, visual acuity
improved 25 letters, ocular coherence thickness improved
from 646 um to 4244 um; structural lesions stabilized
while exudates and edema resolved. Although the results
are somewhat encouraging, it remains to be seen whether
localized VEGF blocking therapy with either bevacizumab
or ranibizumab will be more than an interim solution.
Novel Treatments for VHL disease
The ideal treatment for VHL patients would be gene replacement
therapy, whereby copies of a normal VHL gene
can be introduced into patient’s cells, thereby normalizing
them. At this time, such technology has not yet been
developed for patients with VHL disease, although the
“CRISPR” Cas9 gene editing technology23 shows promise
in an increasingly large number of applications, and
could be adapted for this purpose. Short of replacing defective
VHL, the next best approach would be to block
the HIF transcription factor itself. Two HIF2 alpha blocking
agents PT2385, and the more recent version PT2977,
are in clinical development. PT2385 demonstrated promising
results in a recently published phase I clinical trial
in patients with advanced malignancies.24 PT2977 is
being tested in a phase I clinical study25 (NCT02974738)
and a second study was launched to test this agent in patients
with VHL disease26 (NCT03401788). This latter
study holds great promise for patients with VHL disease,
as HIF blockade would theoretically inhibit development
of all VHL organ manifestations.
Conclusions
Despite the heterogeneous nature of hereditary and sporadic
clear cell RCC, their pathophysiology shares a common
dysregulation of the HIF-VEGF axis. The recognition
of a shared pathway offers the potential to develop an
understanding of the common drivers of tumor progression
and lethality in sporadic and hereditary VHL-related
disease. Although still investigational, ongoing trials
using TKIs and HIF-targeted therapy will hopefully provide
the compelling data needed to support the use of
such therapies in the hereditary VHL patient population.
16 Kidney Cancer Journal
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