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Nature Immunology Paper Highlights Potential Role of FAK Inhibition in Hematological Malignancies
Research from UC Irvine,
“Loss-of-function in the transcription factor Ikaros appears to create a
differentiation block that drives the pre-B cells into an adhesive
state, promotes self-renewal and primes them for malignant potential,”
said
The Nature Immunology article can be accessed at: http://bit.ly/1bKYJ6M.
Human precursor B cell (pre-B cell) acute lymphoblastic leukemia (B-ALL) has an estimated incidence of 8,000 new cases per year in the US of which a substantial portion contain the mutant form of Ikaros.
“Historically, leukemia has been one of the diseases most closely linked
to cancer stem cells,” said
In separate papers published in the
"At Verastem, we are focusing on moving rapidly through late stage
studies in cancers with a defined patient population that are
particularly sensitive to our drug candidates. The Nature Immunology and
Science papers suggest that hematological malignancies could be an added
area where we may be able to help patients in need," said
The Nature Immunology article can be accessed at http://bit.ly/1bKYJ6M and the abstract is below:
Loss of Ikaros DNA-binding function confers integrin-dependent
survival on pre-B cells and progression to acute lymphoblastic leukemia
Published online
Deletion of the DNA-binding domain of the transcription factor Ikaros generates dominant-negative isoforms that interfere with its activity and correlate with poor prognosis in human precursor B cell (pre-B cell) acute lymphoblastic leukemia (B-ALL). Here we found that conditional inactivation of the Ikaros DNA-binding domain in early pre-B cells arrested their differentiation at a stage at which integrin-dependent adhesion to niches augmented signaling via mitogen-activated protein kinases, proliferation and self-renewal and attenuated signaling via the pre-B cell antigen receptor and the differentiation of pre-B cells. Transplantation of polyclonal Ikaros-mutant pre-B cells resulted in long-latency oligoclonal pre-B-ALL, which demonstrates that loss of Ikaros contributes to multistep B cell leukemogenesis. Our results explain how normal pre-B cells transit from a highly proliferative and stroma-dependent phase to a stroma-independent phase during which differentiation is enabled, and suggest potential therapeutic strategies for Ikaros-mutant B-ALL.
The articles from the
How thalidomide works against cancer
Science.
2014 Jan 17;343(6168):256-7
Link: http://bit.ly/19OnNLf
Lenalidomide causes selective degradation of IKZF1 and IKZF3 in
multiple myeloma cells
Jan Krönke,
Science. 2014 Jan 17;343(6168):301-5
Link:
http://bit.ly/1e23bdI
The myeloma drug lenalidomide promotes the cereblon-dependent
destruction of Ikaros proteins
Gang Lu, Richard E.
Middleton,
Science.
2014 Jan 17;343(6168):305-9
Link: http://bit.ly/1eomxji
About VS-6063
VS-6063 (defactinib) is an orally available compound designed to target
cancer stem cells through the potent inhibition of focal adhesion kinase
(FAK). Cancer stem cells are an underlying cause of tumor resistance to
chemotherapy, recurrence and ultimate disease progression. Research by
About VS-4718
VS-4718 is an orally available compound designed to target cancer stem cells through the potent inhibition of focal adhesion kinase (FAK). VS-4718 is currently being studied in a Phase 1 dose escalation study in patients with advanced cancers.
About Verastem, Inc.
Forward-looking statements:
This press release includes forward-looking statements about the
Company’s strategy, future plans and prospects, including statements
regarding the development of the Company’s compounds, including VS-6063,
or defactinib VS-4718, VS-6062 and the Company’s FAK inhibition program,
the timeline for clinical development and regulatory approval of the
Company’s compounds, the expected timing for the reporting of data from
ongoing trials, and the structure of the Company’s planned or pending
clinical trials, and potential indications for clinical development. The
words “anticipate,” “appear,” “believe,” “estimate,” “expect,” “intend,”
“may,” “plan,” “predict,” “project,” “target,” “potential,” “will,”
“would,” “could,” “should,” “continue,” and similar expressions are
intended to identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Each
forward-looking statement is subject to risks and uncertainties that
could cause actual results to differ materially from those expressed or
implied in such statement. Applicable risks and uncertainties include
the risks that the preclinical testing of the Company’s compounds and
preliminary data from clinical trials may not be predictive of the
results or success of ongoing or later clinical trials, that data may
not be available when we expect it to be, that the Company will be
unable to successfully complete the clinical development of its
compounds, including VS-6063 and VS-4718, that the development of the
Company’s compounds will take longer or cost more than planned, and that
the Company’s compounds will not receive regulatory approval or become
commercially successful products. Other risks and uncertainties include
those identified under the heading “Risk Factors” in the Company’s
Annual Report on Form 10-K for the year ended
Source:
Verastem, Inc.
Brian Sullivan, 617-252-9314
bsullivan@verastem.com