The mTOR Inhibitor RAD001 (Everolimus) Inhibits Myeloma Tumor Growth In Vivo and Enhances the Anti-MM Effects of Bortezomib and Arsenic Trioxide.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4801-4801 ◽  
Author(s):  
Richard A. Campbell ◽  
Eric Sanchez ◽  
Jeffrey Steinberg ◽  
Michael Share ◽  
Joseph Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Survival ◽  
Arsenic Trioxide ◽  
Tumor Volume ◽  
Single Agent ◽  
Mouse Serum ◽  
Oral Gavage ◽  
Once Daily ◽  
Tumor Bearing

Abstract The mammalian target of rapamycin (mTOR) is an intracellular protein that acts as a central regulator of multiple signaling pathways (IGF, EGF, PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation, survival and angiogenesis in cancer. mTOR is a critical component of the PI3K/Akt pathway, a key cell survival pathway that is dysregulated in many cancers including multiple myeloma (MM). mTOR is an important therapeutic target because it is a “rate-limiting” bottleneck in the key signaling pathway that regulates cell survival, proliferation, and angiogenesis. RAD001 (everolimus) is a novel oral mTOR pathway inhibitor. Recent data suggests that RAD001 has direct effects on tumor cell proliferation and may have antiangiogenic activity due to inhibition of tumoral VEGF production and effects on vascular endothelial and smooth muscle cell biology. We first evaluated the in vivo effects of single agent RAD001 in mice bearing the human MM tumor LAGλ-1. Tumor-bearing mice receiving RAD001 at 3, 10, or 30 mg/kg once daily five times per week (M-F) via oral gavage showed marked inhibition of tumor growth at all doses (P<0.0001) and reduction of paraprotein levels (P<0.0001) compared to mice receiving placebo. Next, we evaluated the in vivo anti-MM effects of RAD001 in combination with arsenic trioxide (ATO) and RAD001 in combination with bortezomib. Each severe combined immunodeficient (SCID) mouse was implanted with a fragment (2 – 4 mm3) of the LAGλ-1 tumor into the left hind limb muscle. The tumors were allowed to grow for 10 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into treatment groups. Tumor-bearing mice received RAD001 at 1, 3, or 10 mg/kg once daily five times per week via oral gavage, ATO (3 mg/kg) once daily five times per week via intraperitoneal injection, bortezomib (0.5 mg/kg) once daily twice weekly via intravenous injection, or a placebo. Mice receiving RAD001/ATO combination therapy exhibited decreased hIgG levels and tumor volume compared to those mice receiving single agent and placebo therapy. Additionally, those mice receiving the RAD001/bortezomib combination treatment displayed similar MM tumor growth inhibition including decreased hIgG levels and tumor volume as the RAD001/ATO-treated mice. These preliminary in vivo results are encouraging with combination RAD001+ATO and RAD001+bortezomib therapy for the treatment of MM and additional studies are being performed to further optimize the clinical development of RAD001 in combination with other anti-MM treatments for patients with MM.

The Novel Proteasome Inhibitor CEP-18770 Inhibits Myeloma Tumor Growth In Vitro and In Vivo and Enhances the Anti-MM Effects of Melphalan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 843-843
Author(s):  
Eric SancheZ ◽  
Richard A Campbell ◽  
Jeffrey A Steinberg ◽  
Mingjie Li ◽  
Haiming Chen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Tumor Volume ◽  
Single Agent ◽  
Human Tumor ◽  
The Novel

Abstract Proteasome inhibitors (PI) have been shown to be effective agents for the treatment of multiple myeloma (MM) and enhance the anti-tumor effects of a variety of chemotherapeutic drugs including melphalan and doxorubicin as well as arsenic trioxide (ATO). The novel proteasome inhibitor CEP-18770 has recently been shown to induce cytotoxic effects across a broad panel of human tumor cell lines including MM in vitro. However, little data exists on the in vivo anti-MM effects of this PI either alone or in combination with other active anti-MM drugs. First, we examined the anti-proliferative effects of treating MM cell lines in vitro with CEP-18770 alone and in combination with melphalan, arsenic trioxide (ATO) and doxorubicin. MM cell lines were cultured without fetal bovine serum and incubated in the presence of CEP-18770 alone and in combination with these agents for 48 hours. Cell growth was then measured using an MTS assay. First, RPMI8226 and U266 cells were tested in vitro using a constant concentration of melphalan or doxorubicin in combination with varying concentrations of CEP-18770 or varying concentrations of the chemotherapeutic agent with constant CEP-18770. Although single agent treatment showed marked anti-proliferative effects, combination indexes as calculated by the Chou-Talalay method showed synergistic anti- MM effects of CEP-18770 with either melphalan or doxorubicin in these MM cell lines. In addition, similar experiments were carried out evaluating the combination of ATO plus CEP-18770 in RPMI8226 cells and also showed synergism with this combination. Next, a series of in vivo studies were conducted using our SCID-hu models of MM including LAGλ-1, LAGκ-1A and LAGκ-1B. Mice receiving CEP-18770 at 0.1, 0.3, 1, and 3 mg/kg were injected twice weekly via intravenous injection throughout the study. CEP-18770 dosed at 10 mg/kg was administered via oral gavage twice weekly and mice dosed with melphalan received injections once weekly via intraperitoneal injection. Mice bearing intramuscularly implanted LAGλ-1 were treated with CEP-18770 or vehicle alone. Mice treated with the PI inhibited tumor growth as determined by human immunoglobulin (hIg) G levels and measurement of tumor volume (P = 0.0008) compared to mice receiving vehicle. A significant inhibition of both human paraprotein secretion and reduction of tumor growth was also observed in LAGk-1A-bearing mice treated with CEP-18770 at 1, 3 and 10 mg/kg (hIgG: P = 0.0001, P = 0.0002 and P = 0.0001, respectively; tumor volume: P = 0.0001, P = 0.0001 and P = 0.0001, respectively) and LAGk-1B-bearing mice treated with CEP-18770 at 3 and 10 mg/kg (hIgG: P = 0.0008 and P = 0.0034, respectively; tumor volume: P = 0.0008 and P = 0.0028, respectively) compared to mice receiving vehicle. Finally, the combination of CEP-18770 (1 mg/kg) plus melphalan (3 mg/kg) was tested in LAGk-1B-bearing mice. Mice treated with the combination showed markedly smaller tumors compared to treatment with vehicle (P = 0.0008) or melphalan alone (P = 0.0204). Mice treated with the PI alone or in combination with melphalan did not show any observed toxicity. Thus, these studies provide promising preclinical data to suggest the potent anti-MM effects of CEP-18770 both in vitro and in vivo and also suggest that this new PI may enhance the anti-MM effects of several active anti-MM agents including melphalan, doxorubicin and ATO.

scholarly journals Regulation of Parathyroid Hormone-Related Peptide by Estradiol: Effect on Tumor Growth and Metastasis in Vitro and in Vivo

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 2885-2894 ◽  
Author(s):  
S. A. Rabbani ◽  
P. Khalili ◽  
A. Arakelian ◽  
H. Pizzi ◽  
G. Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Volume ◽  
In Vivo Studies ◽  
Promoting Effect ◽  
X Ray ◽  
Tumor Bearing ◽  
Tumor Growth And Metastasis

Abstract We evaluated the capacity of estradiol (E2) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E2 caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E2 tamoxifen. E2 also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E2 production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.

PK11195, a Ligand of the Peripheral Benzodiazepine Receptor, Inhibits Myeloma Cell Growth In Vitro and Chemosensitizes Myeloma Cells In Vivo in SCID-hu Models of Human Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3459-3459
Author(s):  
Richard A. Campbell ◽  
Eric Sanchez ◽  
Haiming Chen ◽  
Lauren Turker ◽  
Olivia Trac ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Tumor Growth ◽  
Single Agent ◽  
Benzodiazepine Receptor ◽  
Peripheral Benzodiazepine Receptor ◽  
Once Daily ◽  
Inhibition Of Tumor Growth

Abstract The peripheral benzodiazepine receptor (mPBR) appears to be a potential target to induce apoptosis in tumor cells. The expression of this receptor has been linked to a poor prognosis in cancer patients. PK11195 may represent a new, well-tolerated potent chemosensitizing agent that affects multiple resistance mechanisms within malignant cells. We have evaluated whether PK11195 inhibits multiple myeloma (MM) cell growth in vitro; and, furthermore, whether this drug can chemosensitize a melphalan resistant human MM tumor, LAGλ-1 (Campbell et al, International Journal of Oncology 2006), to arsenic trioxide (ATO) and melphalan using an in vivo SCID-hu model. The MM cell lines RPMI8226 and U266 were treated with varying concentrations of PK11195 (1 – 100 mM). After incubating with PK11195 for 24 hours, cell growth was measured by MTT assay. Those cells treated with PK11195 showed decreased proliferation at concentrations as low as 1 mM compared to the untreated cells. Next, we investigated the chemosensitizing effects of PK11195 using an in vivo model of human MM. To accomplish this, each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm3 LAGλ-1 tumor fragment into the left superficial gluteal muscle. The tumors were allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum or when tumors became palpable (21 days) and mice were blindly assigned into treatment groups. PK11195 (10, 50 and 100 mg/kg) was administered via oral gavage once weekly when combined with melphalan and once daily five times per week when combined with ATO. Melphalan (3 mg/kg) was administered once weekly via intraperitoneal (i.p.) injection. ATO (1.25 mg/kg) was administered once daily five times per week via i.p. injection. Mice receiving the combination of PK11195 and melphalan (3 mg/kg) showed marked inhibition of tumor growth (PK11195 10 mg/kg, P = 0.03; PK11195 50 mg/kg, P = 0.02; PK11195 200 mg/kg, P < 0.01) compared to mice receiving no therapy. Animals treated with melphalan, as a single agent, did show minimal tumor growth inhibition and reduced paraprotein levels whereas mice treated with single agent PK11195 showed tumor growth similar to the control mice. Mice receiving the combination of PK11195 and low dose ATO (1.25 mg/kg) also showed inhibition of tumor growth (PK11195 200 mg/kg, P < 0.01) whereas treatment with either single agent PK11195 or ATO demonstrated growth similar to the control groups. Treatment with the highest dose of PK11195 (200 mg/kg) was not associated with any observed toxicity suggesting that high doses can be safely administered and are well tolerated. In this study, we showed PK11195 inhibits MM cell growth in vitro at very low concentrations and can chemosensitize drug resistant tumor cells in vivo at doses that have no observable toxicity. We are further evaluating PK11195 as a single agent and in combination therapy both in vitro and in vivo..

The Humanized Anti-CD40 Antibody SGN-40 Inhibits Tumor Growth in LAGκ-1A, a CD40+ Mouse Model of Human Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3506-3506 ◽  
Author(s):  
Richard A. Campbell ◽  
Melinda S. Gordon ◽  
Eric Sanchez ◽  
Haiming Chen ◽  
Lauren Turker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
Tumor Growth ◽  
Murine Model ◽  
Single Agent ◽  
Mouse Serum ◽  
Igg Antibody ◽  
Inhibition Of Tumor Growth

Abstract CD40 is a TNF receptor found on the cell surface of mature B cells (B lymphocytes) and most B-cell malignancies including multiple myeloma (MM). SGN-40 is a high-affinity, humanized monoclonal antibody that targets the CD40 antigen. Recently, it has been shown that SGN-40 decreases the proliferation of malignant B cells by partial agonistic signaling and effector functions in vitro. In this study, we examined the anti-MM effects of SGN-40 in vivo using a CD40+ SCID-hu murine model of human myeloma, LAGκ-1A. Each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm3 LAGκ-1A tumor fragment into the left hind limb muscle. The tumor was allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum. Mice were then randomly assigned to one of four SGN-40 treatment groups (6 mice per treatment group). SGN-40 was administered via intraperitoneal injection twice per week at doses of 0.1, 0.3, 1, and 3 mg/kg. Control mice were given a control IgG antibody (3 mg/kg) using the same schedule. Mice receiving the higher doses of SGN-40 showed marked inhibition of tumor growth (0.3 mg/kg, P < 0.02; 1 mg/kg, P < 0.03; and 3 mg/kg, P < 0.04) and reduction of paraprotein levels (1 mg/kg, P < 0.05; and 3 mg/kg, P < 0.03) compared to mice receiving control antibody. At the lowest dose of SGN-40 evaluated (0.1 mg/kg) a slight inhibition of tumor growth was observable, but there was no effect on human paraprotein. Treatment with SGN-40 was not associated with any observed toxicity. Based on these data with SGN-40 monotherapy, we are currently investigating the antitumor activity of SGN-40 plus bortezomib as well as other available anti-MM agents using our in vivo SCID-hu myeloma murine model. These data for single-agent SGN-40 are encouraging and support testing SGN-40 both alone and in combination regimens to treat MM patients.

The Novel Potent Pan-Deacetylase (DAC) Inhibitor, Panobinostat (LBH589), Markedly Enhances the Anti-Myeloma Effects of Chemotherapy In Vitro and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2520-2520
Author(s):  
Richard A. Campbell ◽  
Eric Sanchez ◽  
Jeffrey Steinberg ◽  
Michael Share ◽  
Joseph Wang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Low Dose ◽  
Liposomal Doxorubicin ◽  
Single Agent ◽  
Mouse Serum ◽  
Once Daily ◽  
Treatment Groups

Abstract Deacetylase (DAC) inhibitors represent a new class of anti-cancer therapeutics that inhibit DAC enzymes and have been shown to have multiple effects in tumor cell lines including decreased oncoprotein expression (Bcr-Abl, HER-2), decreased angiogenesis, induction of apoptosis, induction of cell-cycle arrest, and decreased tumor cell motility and invasion. Panobinostat (LBH589), a novel cinnamic hydroxamic acid analogue with potent histone DAC inhibitor activity, has recently been shown to have the potential to treat a wide range of solid and hematological malignancies including multiple myeloma (MM). In this study, we first evaluated the in vitro anti-MM effects of panobinostat alone and in combination with doxorubicin or melphalan using the MM cell lines RPMI8226, U266 and MM1S. Cells treated with the combinations of panobinostat + doxorubicin and panobinostat + melphalan showed marked synergistic anti-MM effects as determined by measuring proliferation with the MTS assay compared to treatment with single agent and untreated cells. Next, we evaluated the anti-MM effects of panobinostat alone and in these combinations in vivo using one of our SCID-hu mouse models of human MM, LAGλ-1. Each SCID mouse was implanted with a 2.0 - 4.0 mm3 LAGλ-1 into the left superficial gluteal muscle. In our panobinostat single agent study, tumors were allowed to grow for 7 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into panobinostat treatment groups. Panobinostat was administered via intraperitoneal (i.p.) injection once daily five times per week at 5, 10 and 20 mg/kg. Control mice were given sterile normal saline as vehicle. Mice receiving panobinostat showed marked inhibition of tumor growth (10 mg/kg, P &lt; 0.003; 20 mg/kg, P &lt; 0.009) and reduction of paraprotein levels (10 mg/kg, P &lt; 0.0025; 20 mg/kg, P &lt; 0.015) compared to mice receiving vehicle. Next, we evaluated the combination of low-dose panobinostat (5 mg/kg) with low doses of either liposomal doxorubicin (1 mg/kg) or melphalan (3 mg/kg) i.p. in mice bearing LAGλ-1. Tumors were allowed to grow for 10 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into treatment groups. Panobinostat was administered as above, and liposomal doxorubicin was injected once daily for three consecutive days weekly and melphalan once weekly. Mice treated with the combination of panobinostat + liposomal doxorubicin showed markedly smaller tumors and reduced hIgG levels compared to treatment with the DAC inhibitor alone, and treatment with liposomal doxorubicin as a single agent produced no anti-MM effects. Mice bearing LAGλ-1 treated with the combination of low-dose panobinostat + low-dose melphalan also showed markedly smaller tumors and decreased hIgG levels compared to treatment with panobinostat alone whereas mice receiving melphalan alone showed similar results to vehicle-treated animals. These promising results support the further clinical development of panobinostat and suggest that combining this DAC inhibitor with low-dose chemotherapy (liposomal doxorubicin or melphalan) may enhance the efficacy of this novel agent for the treatment of MM patients.

scholarly journals A small-molecule pan-class I glucose transporter inhibitor reduces cancer cell proliferation in vitro and tumor growth in vivo by targeting glucose-based metabolism

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Pratik Shriwas ◽  
Dennis Roberts ◽  
Yunsheng Li ◽  
Liyi Wang ◽  
Yanrong Qian ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Glucose Uptake ◽  
Cancer Cells ◽  
Glucose Transport ◽  
Tumor Volume ◽  
Class I ◽  
Tumor Bearing ◽  
Metabolomics Analysis

Abstract Background Cancer cells drastically increase the uptake of glucose and glucose metabolism by overexpressing class I glucose transporters (GLUT1-4) to meet their energy and biomass synthesis needs and are very sensitive and vulnerable to glucose deprivation. Although targeting glucose uptake via GLUTs has been an attractive anticancer strategy, the relative anticancer efficacy of multi-GLUT targeting or single GLUT targeting is unclear. Here, we report DRB18, a synthetic small molecule, is a potent anticancer compound whose pan-class I GLUT inhibition is superior to single GLUT targeting. Methods Glucose uptake and MTT/resazurin assays were used to measure DRB18’s inhibitory activities of glucose transport and cell viability/proliferation in human lung cancer and other cancer cell lines. Four HEK293 cell lines expressing GLUT1-4 individually were used to determine the IC50 values of DRB18’s inhibitory activity of glucose transport. Docking studies were performed to investigate the potential direct interaction of DRB18 with GLUT1-4. Metabolomics analysis was performed to identify metabolite changes in A549 lung cancer cells treated with DRB18. DRB18 was used to treat A549 tumor-bearing nude mice. The GLUT1 gene was knocked out to determine how the KO of the gene affected tumor growth. Results DRB18 reduced glucose uptake mediated via each of GLUT1-4 with different IC50s, which match with the docking glidescores with a correlation coefficient of 0.858. Metabolomics analysis revealed that DRB18 altered energy-related metabolism in A549 cells by changing the abundance of metabolites in glucose-related pathways in vitro and in vivo. DRB18 eventually led to G1/S phase arrest and increased oxidative stress and necrotic cell death. IP injection of DRB18 in A549 tumor-bearing nude mice at 10 mg/kg body weight thrice a week led to a significant reduction in the tumor volume compared with mock-treated tumors. In contrast, the knockout of the GLUT1 gene did not reduce tumor volume. Conclusions DRB18 is a potent pan-class I GLUT inhibitor in vitro and in vivo in cancer cells. Mechanistically, it is likely to bind the outward open conformation of GLUT1-4, reducing tumor growth through inhibiting GLUT1-4-mediated glucose transport and metabolisms. Pan-class I GLUT inhibition is a better strategy than single GLUT targeting for inhibiting tumor growth.

Efficacy and Tolerability of CEP-18770 in Combination with Dexamethasone and Lenalidomide Using a SCID-Hu Model of Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2946-2946
Author(s):  
Eric Sanchez ◽  
Cydney M Nichols ◽  
Alison C Lam ◽  
Mingjie Li ◽  
Jennifer Li ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Research Funding ◽  
Tumor Volume ◽  
Single Agent ◽  
Volume Growth ◽  
Xenograft Model ◽  
Combination Regimen ◽  
Combination Therapies ◽  
Combination Regimens

Abstract Abstract 2946 Introduction: We previously demonstrated the anti-MM effects of the proteasome inhibitor (PI) CEP-18770 with lenalidomide (LEN) and/or dexamethasone (DEX) using the MM xenograft model LAGκ-1B. Bortezomib has been shown to demonstrate synergistic anti-MM effects with both of these classes of drugs which has led to the successful use of these combinations to treat patients with MM. Thus, we conducted the current study to ascertain the anti-MM effects of CEP-18770 in combination with DEX and/or LEN in vivo using a different human severe combined immunodeficient (SCID) -hu MM model (LAGκ-1A) than then one previously evaluated and mentioned above (LAGκ-1B). Methods: Each naïve SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were randomized into treatment groups based on human immunoglobulin G (IgG) levels. CEP-18770 (4 mg; Cephalon, Inc., Frazer, PA, USA) stock solution was dissolved in propylene glycol (800 μl) and added to 5% mannitol to generate a final stock solution of 1 mg/ml, diluted (5% mannitol). Mice were injected with 1 mg/kg twice weekly (T, Th) via intravenous (i.v.) injection. LEN stock solutions were prepared daily from pills and diluted in 5% carboxymethylcellulose. DEX was obtained as a 4 mg/ml stock solution, diluted (0.9% sodium chloride). Mice were treated daily with DEX at 1.25 mg/kg via intraperitoneal (i.p.) injection and 30 mg/kg of LEN via oral gavage. On a weekly basis, tumor size was measured using standard calipers (n = 9–10 mice/group) and human IgG levels with an ELISA (Bethyl Laboratories, Montgomery, TX). This study was conducted according to protocols approved by the Institutional Animal Care and Use Committee. Results: At day 35 post tumor implantation, mice receiving the doublets of CEP-18770 plus daily dexamethasone or lenalidomide and the triplicate regimen containing all three drugs markedly inhibited tumor volume growth compared to mice receiving vehicle. Notably, P -values could not be calculated because all mice receiving the doublet and triplicate combination regimens had undetectable tumor volumes (zero tumor volume measurements) and thus a t-test could not be calculated. These tumors remained undetectable beginning at day 35 and throughout the study until its termination (day 91). CEP-18770 or DEX administered alone also significantly inhibited tumor volume growth (P = 0.0005, P = 0.0205, respectively) at this same time point, when compared to mice receiving vehicle, whereas LEN alone did not. However, in contrast to the tumors which eventually grew in mice after single agent treatment with CEP-18770, DEX, or LEN and the doublet LEN + DEX group, tumors did not reappear among mice which received the CEP-18770 doublet or CEP-18770 triplicate combination regimens. Similar inhibitory effects were obtained for IgG levels as those observed for tumor volume growth inhibition. Mice receiving CEP-18770 doublets (CEP-18770 + DEX or LEN) or all three drugs together were sacrificed at day 91. Overall, 10/10 mice survived the CEP-18770 + DEX regimen, and 9/10 mice survived in both the CEP-18770 + LEN and CEP-18770 + DEX + LEN groups. Conclusions: These in vivo studies using our LAGk-1A SCID-hu model show that CEP-18770 administered alone, in combination with DEX or LEN, or in triplicate combination with both DEX and LEN, resulted in significant inhibition of tumor growth as determined by measuring tumor volume and IgG levels when compared to vehicle-treated and single agent treated mice. Although the initial anti-MM effects were similar between single agent CEP-18770 and the doublet and triplicate combination therapies, with longer follow-up the doublet and triplicate combination therapies proved to be superior. The toxicity profile was negligible and similar between CEP-18770 monotherapy, combined with either DEX or LEN, and the triplicate combination regimen. Pre and post-treatment body weight comparisons of these groups demonstrated that mice receiving the different treatments gained weight to a similar extent during study treatment. This study demonstrates that using a different MM model (LAGκ-1A), the PI CEP-18770 in combination with DEX and/or LEN results in significant tumor growth and IgG inhibition, and provides further support for the development of the novel agent for the treatment of MM. Disclosures: Berenson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding.

scholarly journals Hematologic effects of flt3 ligand in vivo in mice

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2004-2012 ◽  
Author(s):  
K Brasel ◽  
HJ McKenna ◽  
PJ Morrissey ◽  
K Charrier ◽  
AE Morris ◽  
...  
Keyword(s):  
Single Agent ◽  
Fold Increase ◽  
Time Frame ◽  
Mouse Serum ◽  
Flt3 Ligand ◽  
Hematopoietic Progenitors ◽  
Monocytic Cells ◽  
Once Daily ◽  
Colony Forming Units

We have investigated the effects of in vivo treatment with flt3 ligand (FL) on murine hematopoiesis, including mobilization of progenitors into the peripheral blood (PB). Mice were injected once daily with 10 micrograms recombinant human FL for 15 days. On days 3, 5, 8, 10, 15, and 22, mice were killed and analyzed for the number of leukocytes and colony-forming units (CFU) in bone marrow (BM), spleen, and PB. Splenic and PB cellularity increased with time in FL-treated mice. In the spleen, there was an increase in B cells, myeloid cells, and nucleated erythroid cells; in the PB, there was an increase in lymphocytes, granulocytes, and monocytic cells. The maximal number of CFU in the BM was observed after 3 days of FL treatment, giving 3.7- and 7.3-fold increases in CFU-granulocyte-macrophage (CFU-GM) and CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM), respectively, compared with mouse serum albumin (MSA)-treated controls. After 8 days of FL treatment, there was a maximal 123- and 108-fold increase in splenic CFU-GM and CFU-GEMM, respectively. The maximal number CFU-GM and CFU- GEMM were seen in PB on day 10, with 537- and 585-fold increases, respectively. Burst-forming units-erythroid (BFU-E) increased in the same time frame as those of CFU-GM and CFU-GEMM in BM, spleen, and PB, although the magnitude was not as great. Primitive day-13 CFU-spleen (CFU-S) and phenotypically defined stem cells were also mobilized into the PB of FL-treated mice with similar kinetics and magnitude to that of CFU-GM and CFU-GEMM. We conclude from these studies that FL, when administered as a single agent, is a potent mobilizer of hematopoietic progenitors into the PB.

scholarly journals Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

Oncogene ◽  
2021 ◽  
Vol 40 (11) ◽  
pp. 1957-1973
Author(s):  
Hyunho Yoon ◽  
Chih-Min Tang ◽  
Sudeep Banerjee ◽  
Mayra Yebra ◽  
Sangkyu Noh ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tumor Growth ◽  
Gastrointestinal Stromal Tumor ◽  
Single Agent ◽  
Stromal Tumor ◽  
Paracrine Signaling ◽  
Mesenchymal Transition ◽  
Tumor Growth And Metastasis ◽  
Factor C

AbstractTargeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

scholarly journals Targeting Antibody Checkpoint Fcgriib Using Monoclonal Antibody BI-1206 to Overcome Therapeutic Resistance in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Alexa A Jordan ◽  
Joseph McIntosh ◽  
Yang Liu ◽  
Angela Leeming ◽  
William Lee ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Publicly Traded ◽  
In Vivo Efficacy ◽  
Mantle Cell ◽  
Xenograft Models

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.

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