Over 50% of breast tumors harbor alterations in one or more genes
of the phosphatidylinositol 3-kinase (PI3K) pathway including PIK3CA
mutations (31%), PTEN loss (34%), PTEN mutations (5%) and AKT1 mutations
(3%). While PI3K and mTOR inhibitors are already approved in advanced
breast cancer, AKT inhibitors have been recently developed as a new
therapeutic approach. Capivasertib (AZD5363) is a novel, selective
ATP-competitive pan-AKT kinase inhibitor that exerts similar activity
against the three AKT isoforms, AKT1, AKT2, and AKT3.
Preclinical
studies demonstrated efficacy of capivasertib in breast cancer cell
lines as a single agent or in combination with anti-HER2 agents and
endocrine treatment, especially in tumors with PIK3CA or MTOR
alterations. Phase I/II studies demonstrated greater efficacy when
capivasertib was co-administered with paclitaxel, fulvestrant in hormone
receptor (HR)-positive, HER2-negative breast cancer or olaparib.
The
recommended phase II dose of capivasertib as monotherapy was 480 mg bid
on a 4-days-on, 3-days-off dosing schedule. Toxicity profile proved to
be manageable with hyperglycemia (20-24%), diarrhea (14-17%) and
maculopapular rash (11-16%) being the most common grade ≥3 adverse
events.
Ongoing Phase III trials of capivasertib in combination with
fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib
(CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the
therapeutic role of capivasertib in breast cancer.
Fig. 1
Therapeutic targets in breast cancer.
Highlights
- •
Phosphatidylinositol-3-kinase (PI3K)/Akt (PI3K/AKT) pathway is one of the most commonly altered pathways in breast cancer.
- •
Capivasertib (AZD5363) is a highly potent Akt kinase inhibitor with activity against the three isoforms AKT1, AKT2, and AKT3.
- •
Preclinical
studies demonstrated efficacy of capivasertib either alone or in
combination with anti-HER2 agents, chemotherapy and endocrine treatment.
- •
Dose-limiting toxicities include hyperglycemia (20–24%), diarrhea (14–17%) and maculopapular rash (11–16%).
- •
Capivasertib increased susceptibility to paclitaxel (PAKT, BEECH), fulvestrant (NCT01226316, FAKTION) or Olaparib (ComPAKT).
Abstract
Over
50% of breast tumors harbor alterations in one or more genes of the
phosphatidylinositol 3-kinase (PI3K) pathway including PIK3CA mutations
(31%), PTEN loss (34%), PTEN mutations (5%) and AKT1 mutations (3%).
While PI3K and mTOR inhibitors are already approved in advanced breast
cancer, AKT inhibitors have been recently developed as a new therapeutic
approach. Capivasertib (AZD5363) is a novel, selective ATP-competitive
pan-AKT kinase inhibitor that exerts similar activity against the three
AKT isoforms, AKT1, AKT2, and AKT3. Preclinical studies demonstrated
efficacy of capivasertib in breast cancer cell lines as a single agent
or in combination with anti-HER2 agents and endocrine treatment,
especially in tumors with PIK3CA or MTOR alterations. Phase I/II studies
demonstrated greater efficacy when capivasertib was co-administered
with paclitaxel, fulvestrant in hormone receptor (HR)-positive,
HER2-negative breast cancer or olaparib. The recommended phase II dose
of capivasertib as monotherapy was 480 mg bid on a 4-days-on, 3-days-off
dosing schedule. Toxicity profile proved to be manageable with
hyperglycemia (20–24%), diarrhea (14–17%) and maculopapular rash
(11–16%) being the most common grade ≥3 adverse events. Ongoing Phase
III trials of capivasertib in combination with fulvestrant
(CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and
paclitaxel (CAPItello- 290) will better clarify the therapeutic role of
capivasertib in breast cancer.
Abbreviations
PI3K/AKT pathway, phosphatidylinositol-3-kinaseAkt pathway.
PTEN, phosphatase and tensin homolog.
mTOR, mammalian target of rapamycin.
FDA, Food and Drug Administration.
HR, hormone receptor.
HER2, human epidermal growth factor receptor 2.
RTK, receptor tyrosine kinase.
EGF, epidermal growth factor.
IGF insulin-like growth factor.
PDGF, platelet-derived growth factor.
VEGF, vascular endothelial growth factor.
PH, pleckstrin homology.
TSC2, tuberos sclerosis complex 2.
GSK3β, glycogen synthase kinase-3β.
FoxO, forkhead box class O.
CDK4/6 inhibitors, cyclin-dependent kinase 4/6 inhibitors.
PRAS4, proline-rich Akt substrate of 40 kDa.
ATP, adenosine triphosphate.
IC50, half-maximal inhibitory concentration.
PKA/B/C, protein kinase A/B/C.
IHC, immunohistochemistry.
PK, pharmacokinetic.
AUC, Area Under the Curve.
Cmax, maximum Plasma Concentration.
tmax, time to maximum plasma concentration.
ILC, invasive lobular carcinoma.
IDC, invasive ductal carcinoma.
CBP, CREB-binding protein.
ER, estrogen receptor.
BET, bromodomain and extra-terminal domain.
BRD4, bromodomain-containing protein 4.
InsR. insulin receptor.
IGF-IR, insulin-like growth factor-I receptor.
HER3, human epidermal growth factor receptor 3.
FGFR, fibroblast growth factor receptor.
IGFBP-3, insulin-like growth factor-binding protein 3.
SGK1, glucocorticoid-regulated kinase 1.
PFS, progression-free survival.
TNBC, triple negative breast cancer.
CRPC, castration-resistant prostate cancer.
AR, androgen receptor.
PSA, prostate-specific antigen.
MTD, maximum tolerated dose.
ORR, objective response rate.
AE, adverse event.
CI, confidence interval.
ECG, electrocardiogram.
BRCA, breast cancer gene.
PR, partial response.
SD, stable disease.
OS, overall survival.
HR, hazard ratio.
1. Introduction...
LISÄTIETO molekulaarisesta rakenteesta:
2009-04-28
Modify:
2024-02-10
- 4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide
- AZD5363
- capivasertib
Description
Hormone
receptor (HR) positive, especially
estrogen receptor-positive,
HER2-negative breast cancer is the most common subtype of metastatic
breast cancer, resulting in more than 400,000 deaths annually. Although
endocrine-based therapy is the first line of treatment, resistance
eventually emerges, leaving chemotherapy the only but often ineffective
treatment left. Therefore, significant research has been put into
developing genetically targeted treatments. The PIK3/AKT pathway is one
of the most commonly activated pathways in breast cancer, mainly
through the constitutively active mutation in AKT1, loss of function
mutation in PTEN, a negative regulator of the PIK3/AKT pathway, or
PIK3CA mutations. Therefore, targeting the PIK3/AKT pathway presents a
promising approach for the treatment of breast cancer, leading to the
development of
capivasertib, a pan-AKT kinase inhibitor. On November
17th, 2023, capivasertib, under the brand name TRUQAP, was approved by
the FDA for the treatment of adult patients HR-positive, HER2-negative
locally advanced or metastatic breast cancer with one or more
alterations in PIK3CA/AKT1/PTEN gene(s) in combination with [
fulvestrant].
This approval is based on favorable results obtained from the
CAPItello-291 trial, where the combination of capivasertib and [
fulvestrant] reduced the risk of disease progression or death by 50% versus [
fulvestrant] alone.
Capivasertib is a novel
pyrrolopyrimidine derivative, and an orally available inhibitor of the
serine/
threonine
protein kinase AKT (protein kinase B) with potential antineoplastic
activity. Capivasertib binds to and inhibits all AKT isoforms.
Inhibition of AKT prevents the phosphorylation of AKT substrates that
mediate cellular processes, such as cell division, apoptosis, and
glucose
and fatty acid metabolism. A wide range of solid and hematological
malignancies show dysregulated PI3K/AKT/mTOR signaling due to mutations
in multiple signaling components. By targeting AKT, the key node in the
PIK3/AKT signaling network, this agent may be used as monotherapy or
combination therapy for a variety of human cancers.
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