Notícias e Destaques The Myeloma Matrix Part III (Pre-Clinical)

The Myeloma Matrix Part III (Pre-Clinical)
4.19.07

The IMF is committed to providing a total overview of the "future" as well as the current state of myeloma treatments. The printed version of the Myeloma Matrix provides updated information about drugs beginning with pre-clinical developments, tracks drugs as they proceed through Phases I-III of clinical trials, and provides information on trials that are being conducted by NCI-sponsored cooperative groups as well as other myeloma study groups. Call the toll-free hotline (800) 452-2873 for your printed copy.

  • Pre-clinical—Testing of new therapies in a laboratory setting prior to testing on human subjects.
  • Phase I—Assess side effects of the treatment and determine a maximum tolerated dose.
  • Phase II—Assess anti-myeloma effects of treatment at the dose established in Phase I trial.
  • Phase III—Compare a newer treatment against current standard treatment.
PHASE
BRAND NAME
(OTHER NAME)
COMPANY
(SPONSOR)
INDICATION
Pre-Clinical
1D09C3 GPC Biotech, AG Human monoclonal antibody; clinical trials second half of 2004.
ABT737 Abbott Small molecule Bcl-2 inhibitor that also overcomes resistance to proteasome inhibition.
ACE-011
Acceleron Pharma
Protein based on activin receptor IIA that works by both inhibiting bone loss and stimulating bone formation; currently in Phase I trials for healthy post-menopausal women.
Actemra® (tocilizumab injection)
Chugai Pharmaceutical Company; Hoffman-La Roche
Anti-human IL-6 receptor monoclonal antibody approved for treatment of Castleman’s Disease being studied in rheumatoid arthritis, Crohn’s Disease, and myeloma .
Ad-p53/GM-CSF/B7-1
immunotherapy
Beijing Institute of Radiation Medicine
Recombinant adenovirus carrying human wild-type p53, granulocyte-macrophage colony-stimulating factor, and B7-1 genes.
AMG523 Amgen B-cell activating factor (BAFF) inhibitor active in MM cell lines.
Antigen-loaded
dendritic cell
vaccine
National Cancer Institute and Aastrom Biosciences Idiotype vaccination following allogeneic transplant.
Anti-CD 32B
monoclonal antibody
MacroGenics Monoclonal antibody against low-affinity Fc receptor for use in the treatment of hematologic cancers
anti-DKK1
UAMS
DKK1 neutralizing antibodies reduce osteolytic bone resorption, increase bone formation, and help control myeloma growth in lab mice.
AP23841 ARIAD Pharmaceuticals Small molecule inhibitor of osteolclasts.
APOMINE™
(SR-45023A)
ILEX Bisphosphonate ester.
AT-101
Ascenta Therapeutics, Inc.
Orally available pan-Bcl-2 inhibitor demonstrated significant anti-myeloma activity in vitro at Mayo Rochester.

AZD6244
(ARRY-142886)

Astra Zeneca

MEK 1/2 inhibitor which inhibits the proliferation and survival of human MM cell lines.

BIBF 1000
(indolinone)
Boehringer Ingelheim Pharma GmbH Targeted kinase inhibitor that induces apoptosis in t(4;14)-positive cell lines.
BIRB 796
Buchringer Ingelheim Pharmaceuticals
p38 MAPK inhibitor that overcomes drug resistance in the bone marrow microenvironment
bisphosphonate
conjugates
MBC Pharma
Compound drugs that couple a bisphosphonate with an anticancer agent to target bone and/or surrounding tissue.
BLyS/rGel Targa Therapeutics Fusion protein of an antibody tethered to a toxin for the potential treatment of myeloma and autoimmune diseases.
CD32B Mab
MacroGenics, Inc.
Monoclonal antibody targeted against CD32B; may have therapeutic potential in B-cell malignancies (NHL, CLL, MM).
CD74-DOX
conjugate
(anti-CD74
monoclonal
antibody
conjugated
with doxorubicin)
Immunomedics, Inc. Therapy targeted to CD74-expressing MM cells lines

Chaetocin

Mayo Clinic
A fungal toxin that demonstrates potent anti-myeloma activity through oxidative stress and consequent apoptosis induction.
cKap
PacMab Ltd.
Chimeric version of the murine antibody, mKap, that induces apoptosis in all myeloma cell lines shown to express the surface antigen KMA. cKap is highly effective in inducing antigen-dependent cellular cytotoxicity.
CP-533,536 Pfizer Triggers healing of fractures and bone defects.
CPHPC Royal Free Hospital, London Binds to serum amyloid P compound to prevent amyloid deposition.
CPS11 & CPS49
Celgene
Thalidomide analogs developed at University of Leipzig and licensed to Celgene .
CRB-15
(IL-15 cytokine
receptor blocker)
Roche, Cardion AG Targeted against IL-15 receptor to prevent transplant rejection.
Cyclopamine
Johns Hopkins
Developmental Hedgehog pathway antagonist that kills cancer stem cells.
DOM 1112
Domantis
Dual targeting domain antibody (dAb) directed against CD38 and CD138 for the potential treatment of mm.
EGCG
(epigallocatechin-3-gallate)
Dana-Farber, VA Boston Polyphenol extracted from green tea induces growth arrest and apoptosis in myeloma cells.
Enzastaurin (LY317615.Hcl)
Lilly
Oral PKC-inhibitor that inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients.
Factor 5A
(Eukaryotic
Translation Initiation
Factor 5A1)
Senesco Technologies, Inc. Controls formation of proteins required for cell death.
Fludelone (Flu)
Memorial Sloan-Kettering Cancer Center
Synthetic epothilone that eradicates myeloma cells grafted in mice.
Ganoderma
Cedars-Sinai Medical Center; University Hospital, Freiburg Mushroom extract with antiproliferative activity against leukemia, lymphoma, and myeloma.
Geldanamycin
(GA)
National Cancer Institute Inhibits proteins that protect cancer cells from effects of therapy.
GRN163 Ribozyme Pharmaceuticals, Inc. and Geron Corporation Telomerase inhibitor.
GX15-070
Gemin X Biotechnologies, Inc.
Pan-Bcl-2 inhibitor found to induce apoptosis in 12/12 myeloma cell lines tested by A. Keith Stewart et al. at Mayo Scottsdale.
highly purified hematopoietic
stem cells
(HSCs)
Cellerant Therapeutics, Inc. Eliminates cancer cells and T-cells from HSCs used in transplant.
hLL1 Immunomedics Humanized monoclonal antibody targeted to the CD74 receptor.
honokiol (HNK)
Dana-Farber Cancer Institute Traditionally used in Chinese and Japanese medicine and derived from magnolia; cytotoxic to myeloma cell lines.

HuLuc63

PDL
Biopharma, Inc
& Dana-Farber

Novel humanized monoclonal antibody to CS1, a myeloma antigen expressed in more than 96% of mm patients.

HuMax-CD38
(human IgG1,k antibody)
Genmab A/S Antibody to the CD 38 molecule, which is highly expressed on the surface of mm cells.
Imexon University of Arizona Induces apoptosis, oxidative stress, and mitochondrial alterations in myeloma cells.
IMMU-110
Immunomedics, Inc. Humanized monoclonal antibody conjugated with doxorubicin and targeted to CD74 antigen.
ISIS 345794
Isis Pharmaceuticals
Antisense drug targeting STAT-3
ispinesib
Cytokinetics
Novel inhibitor of kinesin spindle protein (KSP) induces cell death in MM cells, and overcomes resistance to conventional drugs and novel agents.
JS-K (JS-kappa)
Dana-Farber Cancer Institute
Prodrug designed to release nitric oxide that shows significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines.
KT-5720 Chaim Sheba Medical Center
(Israel)
Reverses multidrug resistance in cells from patients with MM. Good candidate for combination therapy.
LBH589
Novartis
HDAC inhibitor that induces apoptosis in myeloma cells resistant to conventional therapies and has significant synergistic cytotoxicity with bortezomib (Velcade).
LBW242
Novartis; Dana-Farber
A low molecular weight second mitochondria-derived activator of caspases (smac) that promotes apoptosis in myeloma cells resistant to conventional and bortezomib therapies.
L-NAME
(N-G-nitro-L-
arginine
methyl ester )
Kumamoto University
(Japan)
Nitric oxide synthase inhibitor.
LS 104
LymphoSign
Kinase inhibitor that is active in myeloma in vitro.
mAb, C11C1 Temple University School of Medicine Monoclonal antibody to kininogen may improve the efficacy of conventional mm treatment with minimal side effects.
mAb, ICAM-1 Abiogen Monoclonal antibody being evaluated in Italy for the potential treatment of myeloma.
MGCD0103
MethylGlene Inc.
HDAC inhibitor active against myeloma cell lines in combination with interferon alpha.
MMF
(mycophenolate mofetil)
University of Maryland IMP dehydrogenase inhibitor active against myeloma cells in vitro.
MOR202 MorphoSys AG Antibody targeting molecule CD38
MyelomaCide_
Y-90
Immunomedics, Inc. Y-90-labeled antibody.
NVP-LAQ824 Novartis Histone deacetylase inhibitor.
parthenolide (PTL)
Indiana University; Sapporo Medical University
Extract from feverfew that strongly induces apoptosis in MM cell lines
Patupilone
(epothilone B,
EPO906
Novartis A novel chemo agent that inhibits growth and survivial of myeloma cells,including those resistant to conventional chemo.
PD173074
Glaxo Smith-Kline
Small molecule fibroblast growth factor receptor inhibitor that inhibits the growth of two t(4;14)-positive MM lines.

PD 0332991

Pfizer
Orally active small molecule that inhibits enzymes and proteins in the myeloma cell.
pemetrexed (Alimta®)
Eli Lilly
FDA-approved antifolate chemo agent (for second-line therapy of non-small cell lung cancer) demonstrates potent anti-myeloma effect on cell lines and fresh cells from patients resistant to conventional agents
PHI 380 Parker Hughes Cancer Center Phenylarsonic acid derivative that causes apoptotic death to cell lines of various cancers, including myeloma.

PKC412

Novartis Tyrosine kinase inhibitor that targets fibroblast growth factor.
PPAR-gamma
ligands (15d-PGJ2
and ciglitazone)
University of Rochester Antidiabetic therapies that induce MM cell apoptosis
PPP
(picropodophyllin)
Vrije University of Brussels
Cyclolignan that inhibits IGF-1R tyrosine kinase and reduces proliferation and angiogenesis of MM cells.
PRO-001 Prochon Biotech Ltd. Anti-FGFR3 neutralizing antibody that is cytotoxic to t(4;14)-positive MM cells.
PTK787 Novartis and Schering, AG Inhibitor of VEGF tyrosine kinases.
raloxifene
(Evista®)
University of Liege Selective estrogen receptor modulator that induces myeloma cell cycle arrest and apoptosis.
recombinant human
Mannose-Binding
Lectin (rhMBL)
Enzon
For the treatment of severe infections in patients with mm and others who are MBL deficient.
resveratrol
(trans-3,4’,5-
trihydroxystilbene)
Southern Denmark University Network & Odense University Hospital
Polyphenol found in grapes and red wine that is active against myeloma cell lines

Reversine (2-(4-
Morpholinoanilino)-6-
cyclohexylaminopurine)

Dana-Farber Cancer Institute

Small molecule that may represent a distinct class of agents with therapeutic potential for specific subsets of MM.

Sarasar ™, (lonafarnib, SCH66336)
Schering-Plough
Farnesyltransferase inhibitor (FTI)
SDX-101
(R-etodolac)
Salmedix Single component of the anti-inflammatory drug etodolac; circumvents drug resistance in MM cell lines.
SDX-308
Salmedix
More potent analog of the non-steroidal anti-inflammatory drug SDX-101 (R-etodolac); inhibits osteoclast formation and myeloma cell proliferation.
seliciclib (CYC202,
R-roscovitine)
Cyclacel Oral cyclin dependent kinase inhibitor.

SF1126

Semafore

Novel RGD targeted derivative of LY294002 with significant antiangiogenic activity in MM cells.

skeletally
targeted
proteasome
inhibitors
(bone-targeting
nanocapsules)
US Department of Defense. Southwest Research Institute and UT Health Science Center
Targeting proteasome inhibitors to myeloma lesions in bone via nanocapsules.
StemEx Gamida Cell Hematopoietic support in patients with relapsed or refractory hematologic malignancies who are receiving high-dose therapy.
SU5402
Sugen
Fibroblast growth factor receptor inhibitor that inhibits the growth of two t(4;14)-positive MM lines.
Sutent®
(sunitinib, SU11248)
Pfizer
Approved drug for renal cell carcinoma and GIST demonstrates antitumor effects in hematological malignancies, especially in combination with rapamycin analogue RAD001.
Tc-99m-MIBI
(technecium-99m
2-methoxy-
isobutylisonitrile)
Uludag University
(Turkey)
Sensitive imaging (scanning) technique.
thioredoxin antisense
molecules
Lorus Therapeutics, Inc. Reduces level of thioredoxin.
Thymoglobulin
(rabbit-derived
polyclonal anti-
thymocyte globulin)
SangStat Medical Corp.
Drug approved for treatment of kidney transplant rejection shows activity against myeloma cell lines in vitro and in vivo.
TRAIL-RlmAb Human Genome Sciences Binds to TRAIL, a TNF. Cleared by FDA for Phase I trial.
Treosulfan University of Muenchen Alkylating agent.
trichostatin A (TSA)
University of Maryland
Histone deacetylase inhibitor that sensitizes TRAIL-resistant myeloma cells to remove the obstacles to programmed cell death.
Tubacin
(aggresome inhibitor)
Dana-Farber Cancer Institute and Broad Institute of MIT Blocks the function of histone deacetylase 6; used with bortezomib as an alternative protein disposal inhibitor
ULBP2-BB4
University Hospital Cologne
Novel recombinant bispecific protein that strongly activates primary NK cells.

VE465

Vertex/Merck

Aurora kinase inhibitor that is active in vitro against MM cell lines and/or primary MM tumor cells resistant to various anti-myeloma therapies.

Zolinza
(vorinostat, SAHA)
Merck
HDAC inhibitor that has already been approved for cutaneous T-Cell lymphoma and is now being studied in myeloma in combination with bortezomib (Velcade).
The Myeloma Matrix is brought to you in part
by grants from
Millennium Pharmaceuticals, Celgene Corporation,
and Ortho Biotech.
© 2005-2006 The International Myeloma Foundation