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Page 4 of 16 Fetro. Rare Dis Orphan Drugs J 2023;2:7 https://dx.doi.org/10.20517/rdodj.2023.06

Cancer-associated PIK3CA gene mutations result in the production of an altered p110 alpha subunit.
Strongly and permanently activated due to the presence of a gain-of-function mutation in PIK3CA, p110
alpha allows the Phosphatidylinositol 3-Kinase (PI3K) to signal without regulation, promoting oncogenesis
[14]
and tissue overgrowth . Patients with PIK3CA-mutated, hormone receptor (HR)-positive/HER2-negative
tumors have poor outcomes and resistance to chemotherapy .
[15]
Developed by Novartis, alpelisib was approved by the United States Food and Drug Administration (FDA)
as Piqray® in combination with fulvestrant for advanced or metastatic breast cancer with a PIK3CA
mutation. Fulvestrant is a selective estrogen receptor antagonist which works both by down-regulating and
degrading the estrogen receptor. Piqray® is used with fulvestrant after hormone treatment used alone has
failed.

Activating PIK3CA mutations are also found in overgrowth syndromes, collectively known as PIK3CA-
related overgrowth spectrum (PROS). PROS includes a group of genetic disorders and various clinical
entities that leads to the overgrowth of various body parts due to mutations in the PIK3CA gene. The
CLOVES (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal
anomalies) syndrome, a rare disorder first described as a distinct syndrome, is, for instance, one subtype of
this spectrum.

The severity of PROS is highly variable, ranging from localized overgrowth to severe, extensive, and life-
threatening overgrowth affecting major vessels and/or critical organs.

PIK3CA-related cancers and PROS share the same pathogenetic mechanism and almost the same PIK3CA
[14]
mutational profile .

PI3K/AKT/mTOR pathway is involved in many biological processes, including cell metabolism,
proliferation, survival, and growth; deregulation of PI3K/AKT/mTOR pathway functioning, in the sense of
overactivity, promotes oncogenesis and tissue overgrowth .
[16]

It is then relevant to investigate the potential of some anticancer drugs to treat rare overgrowth syndromes
such as PROS.

As in cancer, PIK3CA mutations in PROS occur as post-zygotic events, but unlike in cancer, these
mutations arise during embryonic development . Different components of the PI3K/AKT/mTOR
[17]
signaling pathway can be specifically targeted to treat PROS. The PIK3CA protein is involved in the first
intracellular signal transduction step of the mTOR pathway. Alpelisib acts at the top of the PI3K/AKT/
mTOR signaling pathway and sirolimus, a direct inhibitor of mTOR, at the end of the PI3K/AKT pathway
[14]
[Figure 1]. Both molecules were tested in PROS .
However, since activation of mTOR is responsible for some but not all of the biological effects caused by
PI3K gain-of-function, alpelisib proved to be a more attractive drug candidate in PROS by providing a
direct outcome on affected tissues while reducing the risk of off-target effects.

Alpelisib (BYL719) was in a phase III randomized double-blind, placebo-controlled study (SOLAR-1)
conducted in patients with PIK3CA-mutated, HR-positive, human epidermal growth factor receptor 2-
negative advanced breast cancer with a tolerable safety profile when Canaud’s research group decided to
explore its therapeutic potential in PROS. After achieving impressive outcomes first on PROS mouse