Targeting CD44 in the bone marrow microenvironment of MM

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$218,817.00
Award Year:
2012
Program:
SBIR
Phase:
Phase I
Contract:
1R43CA171367-01A1
Award Id:
n/a
Agency Tracking Number:
R43CA171367
Solicitation Year:
2012
Solicitation Topic Code:
NCI
Solicitation Number:
PA12-088
Small Business Information
3802 Spectrum Boulevard, Suite 124, Tampa, FL, 33612-9220
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
968675244
Principal Investigator:
RAJESHNAIR
(813) 453-8993
rajesh.nair@gmail.com
Business Contact:
RAJESHNAIR
(813) 453-8993
rnair@gmail.com
Research Institute:
Stub




Abstract
DESCRIPTION (provided by applicant): The majority of multiple myeloma (MM) patients will initially respond to standard chemotherapy. However, eventually relapse of the disease, associated with a multi-drug resistant phenotype, contributes to poor clinicaloutcomes. Our laboratory has recently discovered that a d-amino acid containing peptide, HYD1, blocks adhesion of myeloma cells to extracellular matrices and induces necrotic cell death. Importantly, ex-vivo HYD1 demonstrates increased potency in MM cellsobtained from relapsed patients compared to newly diagnosed, indicating that this novel class of compounds may be an effective strategy for the treatment of relapsed myeloma patients. We have recently cyclized the linear HYD1 peptide which we refer to as cHYD1 binds. cHYD1 binds to the extracellular domain of recombinant CD44 with a KD value of 5 nM. Furthermore, biotin conjugated peptide pulls down a CD44/VLA-4 containing complex using membrane extracts obtained from MM cell lines. CD44 is known to regulate integrin mediated adhesion, trafficking of leukocytes, survival, and differentiation. We propose that the dual function of blocking matrix mediated cell adhesion and inducing cell death provides evidence that cHYD1 is an attractive novel class of anti-cancer agents. Furthermore, we hypothesize, based on the biology of the target, that cHYD1 will disrupt the MM niche. It is well known that the MM niche is critical for disease progression and emergence of drug resistance and agents that disrupt the niche are needed to improve standard therapy. The goal of specific aim 1 of this proposal will be to determine the efficacy of cHYD1 in combination with bortezomib, using immune competent in vivo models. The goal of specific aim 2 will be to determine the effect of cHYD1 on disrupting specific components of the MM niche. PUBLIC HEALTH RELEVANCE: Clinical outcomes strongly support the need for the development of novel strategies for the treatment of this deadly disease. To this end this proposal will determine whether the cyclized peptide referred to as cHYD1 is an attractive strategy to combine with standard therapy for the treatment of myeloma.

* information listed above is at the time of submission.

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