Publication Identifies Cyclin E as Key Resistance Pathway to Breast Cancer Treated by CDK4/6 Inhibitors and Thereby Amenable ...
March 25 2019 - 7:00AM
-- PALOMA-3 study gene expression
profiling shows that CDK2 is a key kinase bypass mechanism
after treatment with palbociclib plus hormone therapy
--
Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP)
(Cyclacel or the Company), a biopharmaceutical company developing
innovative medicines based on cancer cell biology, highlighted a
paper from independent investigators titled Cyclin E1 Expression
and Palbociclib Efficacy in Previously Treated Hormone
Receptor–Positive Metastatic Breast Cancer published in the most
recent edition of the Journal of Clinical Oncology (Turner N et al,
2019 https://ascopubs.org/doi/full/10.1200/JCO.18.00925). The study
findings identify overexpression of cyclin E1 as a mechanism by
which breast cancer escapes the effects of palbociclib CDK4/6
inhibitor (Ibrance®) plus fulvestrant treatment. Inhibition of the
CDK2/cyclin E complex, the target of Cyclacel’s CYC065 clinical
stage candidate, is proposed as a potential therapeutic approach to
prevent early progression on CDK4/6 inhibitors.
“These data from a successful, randomized Phase
3 study identifies cyclin E as a biomarker of resistance of
estrogen receptor positive, HER-2 negative breast cancer to
palbociclib regimens. This supports and extends previous data
showing that cyclin E is a resistance mechanism to HER-2 positive
breast and uterine cancer treated with trastuzumab,” said Spiro
Rombotis, President and Chief Executive Officer of Cyclacel.
“Preclinical data demonstrated CYC065 activity in cyclin E
amplified models of palbociclib-resistant breast cancer. Tumor
shrinkage and stable disease were observed in four patients with
cyclin E amplified advanced cancers in a first-in-human, Phase 1
study of single agent CYC065. Cyclin E amplified tumors are found
in patients with gynecological and other cancers and represent a
large, unmet medical need. The findings support CYC065’s broad
therapeutic potential and unique target profile among CDK
inhibitors.”
In the PALOMA-3 trial (NCT01942135), patients
with endocrine therapy-pretreated, metastatic breast cancer were
randomized to receive palbociclib + fulvestrant or placebo +
fulvestrant. Out of 521 patients treated 302 had tumor tissue
analyzed. Palbociclib efficacy was approximately halved in
patients with high compared to low cyclin E1 expression in their
tumors (median PFS of 7.6 vs. 14.1 months respectively). In
contrast to cyclin E1 expression, the analysis showed that
expression of cyclin D1, the molecular partner of CDKs 4 and 6
which are the targets of palbociclib, or PI3 kinase (PIK3CA)
mutations were not predictive of efficacy for palbociclib plus
hormone therapy.
The findings were further validated through a
gene expression analysis of the Preoperative Palbociclib (POP)
trial in 61 patients with untreated early-stage breast cancer
receiving either palbociclib until the day before surgery or no
treatment. High cyclin E expression was associated with lower
absolute antiproliferative response to palbociclib (high 36%;
intermediate 79%; low 80%; P = 0.005). Correlative analysis of
PALOMA-3 data has identified cyclin E1 as the first potential
biomarker that is predictive of the efficacy of palbociclib.
About CYC065
CYC065 is a highly-selective, orally- and
intravenously-available, 2nd generation inhibitor of cyclin
dependent kinases (CDK) 2 and 9. CYC065 is in an ongoing Phase 1,
first-in-human study in patients with advanced solid tumors. In
this study target engagement and durable suppression of the Mcl-1
biomarker were observed after a single dose of CYC065. Tumor
shrinkage and stable disease were observed in four patients with
cyclin E amplified advanced cancers. CYC065 is also being evaluated
in a Phase 1 study in combination with venetoclax in patients with
relapsed/refractory CLL. Preclinical data suggest that CYC065 may
benefit patients with adult and pediatric hematological
malignancies such as CLL, AML, ALL, B-cell lymphomas, multiple
myeloma and certain cyclin E-addicted or MYC-amplified solid
tumors, including HER2+ breast cancer, uterine serous carcinoma and
neuroblastoma.
About Cyclacel Pharmaceuticals,
Inc.
Cyclacel Pharmaceuticals is a clinical-stage
biopharmaceutical company using its expertise in cell cycle,
transcriptional regulation and DNA damage response biology in
cancer cells to develop innovative medicines. The transcriptional
regulation program is evaluating CYC065, a CDK inhibitor, in
patients with advanced solid cancers and in combination with
venetoclax in patients with advanced hematological malignancies,
including CLL and AML. The DNA damage response program is
evaluating a sequential regimen of sapacitabine and seliciclib, a
CDK inhibitor, in BRCA positive patients with advanced solid
cancers and a concomitant regimen of sapacitabine and olaparib, a
PARP inhibitor, in BRCA positive patients with breast cancer.
CYC140, a PLK inhibitor, is in a Phase 1 first-in-human study in
patients with advanced leukemias. Cyclacel's strategy is to build a
diversified biopharmaceutical business focused in hematology and
oncology based on a pipeline of novel drug candidates. For
additional information, please visit www.cyclacel.com.
Forward-looking Statements
This news release contains certain
forward-looking statements that involve risks and uncertainties
that could cause actual results to be materially different from
historical results or from any future results expressed or implied
by such forward-looking statements. Such forward-looking statements
include statements regarding, among other things, the efficacy,
safety and intended utilization of Cyclacel's product candidates,
the conduct and results of future clinical trials, plans regarding
regulatory filings, future research and clinical trials and plans
regarding partnering activities. Factors that may cause actual
results to differ materially include the risk that product
candidates that appeared promising in early research and clinical
trials do not demonstrate safety and/or efficacy in larger-scale or
later clinical trials, trials may have difficulty enrolling,
Cyclacel may not obtain approval to market its product candidates,
the risks associated with reliance on outside financing to meet
capital requirements, and the risks associated with reliance on
collaborative partners for further clinical trials, development and
commercialization of product candidates. You are urged to consider
statements that include the words "may," "will," "would," "could,"
"should," "believes," "estimates," "projects," "potential,"
"expects," "plans," "anticipates," "intends," "continues,"
"forecast," "designed," "goal," or the negative of those words or
other comparable words to be uncertain and forward-looking. For a
further list and description of the risks and uncertainties the
Company faces, please refer to our most recent Annual Report on
Form 10-K and other periodic and other filings we file with
the Securities and Exchange Commission and are available
at www.sec.gov. Such forward-looking statements are current
only as of the date they are made, and we assume no obligation to
update any forward-looking statements, whether as a result of new
information, future events or otherwise.
Contacts
Company: Paul McBarron, (908) 517-7330,
pmcbarron@cyclacel.comInvestor Relations: Russo Partners LLC,
Alexander Fudukidis, (646) 942-5632,
alex.fudukidis@russopartnersllc.com
© Copyright 2019 Cyclacel Pharmaceuticals, Inc.
All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks
of Cyclacel Pharmaceuticals, Inc. Ibrance® is a registered
trademark of Pfizer, Inc.
Cyclacel Pharmaceuticals (NASDAQ:CYCC)
Historical Stock Chart
From Aug 2024 to Sep 2024
Cyclacel Pharmaceuticals (NASDAQ:CYCC)
Historical Stock Chart
From Sep 2023 to Sep 2024