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Mark Pegram

Publications and source records attributed to Mark Pegram.

14 recordsLinked to original sources
PubMed2006

Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo.

Clinical studies indicate that Herceptin (trastuzumab), a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase growth factor receptor, provides a significant but transient survival advantage to a subset of patients with HER-2-overexpressing metastatic breast cancer when given as a first-line agent. Increased insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has recently been identified as a potential factor adversely influencing the response to Herceptin. We examined the effect of recombinant human IGF binding protein 3 (rhIGFBP-3), an antagonist of IGF-IR signaling, in Herceptin-resistant breast cells in vitro and in tumors in vivo. Consistent with results obtained using HER-2- or IGF-IR-transfected cells (MCF-7/HER2-18 and SKBR3/IGF-IR, respectively), we found that rhIGFBP-3 significantly reduced IGF-I-induced IGF-IR phosphorylation and displayed a synergistic interaction with Herceptin against cultured HER-2-overexpressing breast cancer cells in vitro. We show, for the first time, the antitumor activity of rhIGFBP-3 against advanced-stage MCF-7/HER2-18-transfected human breast cancer xenografts and its potentiation of Herceptin activity. We also provide evidence that IGF-IR activation counters the early suppressive effect of Herceptin on HER-2 signaling via Akt and p44/p42 mitogen-activated protein kinase (MAPK), and that inhibition of HER-2-overexpressing human breast tumor growth by rhIGFBP-3 is associated with restored down-regulation of Akt and p44/p42 MAPK phosphorylation in vitro and in vivo. These results emphasize the merit of evaluating simultaneous blockade of the HER-2 and IGF-IR pathways using combination therapy with rhIGFBP-3 plus Herceptin in human clinical trials of patients with HER-2-positive breast cancer.

Antibodies, Monoclonal↗
PubMed2006

Application and potential limitations of animal models utilized in the development of trastuzumab (Herceptin): a case study.

The preclinical and clinical development of trastuzumab, a humanized monoclonal antibody directed against a juxtamembrane epitope in the HER2 receptor ectodomain, relied heavily on the use of animal models to validate HER2 as a potential MAb target. The identification of HER2 (neu) as a proto-oncogene was first established in a carcinogen-induced brain tumor in the rat. Transgenic mouse technology led to an understanding of the role of HER2 in pathogenesis of breast cancer. Transfection studies of human HER2 cDNA into murine xenograft models further explored the role HER2 plays in tumor progression and metastasis. A murine subrenal capsule fresh human tumor explant assay was utilized to test efficacy of various murine monoclonal anti-HER2 antibodies, and the data were helpful in choosing the most efficacious for subsequent human engineering for clinical use. HER2-overexpressing xenograft models in athymic mice were used to test the efficacy of anti-HER2 antibodies, develop dose-response relationships, measure drug interactions between trastuzumab and chemotherapy, and optimize dosing schedules of chemotherapeutics combined with trastuzumab. In this work, we will highlight the utility of animal models exploited in the development of trastuzumab - noting not only their contribution to drug development but also their limitations in translation of preclinical data into the clinic. It is likely that the experience we gained in the case of preclinical animal models to study in vivo effects of trastuzumab have parallels in the development of other monoclonal antibodies since overcoming the species boundaries (i.e. cross-reactivity with antigenic determinant, development of cross-species neutralizing antibodies, and cross-species interaction with activating Fc receptors on immune effector cells) are major limitations in the design and interpretation of preclinical/translational experiments designed to fulfill various regulatory requirements prior to initiation of phase I human clinical trials.

Animals↗
PubMed2006

Targeting HER2 Epitopes.

Variable expression of the HER2 receptor has been implicated in the pathogenesis of a number of malignancies. Many therapeutic modalities have been devised that target the receptor and downstream molecular pathways. The humanized monoclonal antibodies trastuzumab and pertuzumab bind epitopes on the extracellular domain, resulting in cell growth inhibition though a number of proposed mechanisms. Peptidomimetic agents represent short amino acid sequences containing structural features of the antibody complementarity determining regions (CDRs), and appear to have similar inhibitory properties in experimental models. RNA aptamers are ribonucleotide sequences that also exhibit complementarity with extracellular epitopes and lead to growth inhibition. Recent data suggest a synergistic interaction of HER2 epitope-targeting agents when used in combination.

Animals↗
PubMed2005

Epidermal growth factor receptor and signal transduction: potential targets for anti-cancer therapy.

Agents targeting the epidermal growth factor receptor (EGFR) pathway hold particular promise for the treatment of patients with advanced disease, for whom standard chemotherapy is generally palliative. Expression of EGFR on numerous types of solid tumors, and the association of EGFR activation with tumorigenic processes including proliferation, anti-apoptosis and metastatic spread, make this pathway a particularly compelling target for rational drug design. The two classes of anti-EGFR agents in late-stage clinical testing include antibodies directed toward the extracellular EGFR domain (cetuximab, panitumumab) and small molecule tyrosine kinase inhibitors (gefitinib, erlotinib), which inactivate the receptor enzyme activity. However, important issues remain to be addressed. These include the development of appropriate predictive markers for response, such as improved tests for EGFR activity, correlation of rash with response and potential pharmacogenomic approaches; the sequencing and combination of these agents with chemotherapy and irradiation; and the possible role of these agents in the treatment of patients with earlier stage disease.

Animals↗
PubMed2005

Reducing the global breast cancer burden: the importance of patterns of care research.

Breast cancer treatment guidelines are not uniformly followed in clinical practice, with evidence for substantial variations in treatment patterns, quality of care, and patient outcomes among and within countries. The factors that drive treatment decisions are unclear. Furthermore, the impact of different treatment strategies on survival is poorly understood outside the clinical trial setting. Sources of patterns of care information often have limitations in completeness, quality, timeliness of reporting, and relevance to the larger population. Patterns of care studies frequently lack details on cancer stage at diagnosis, tumor biology, and treatment received. It is difficult to compare data between studies and/or track changes over time because of variations in data sources and collection techniques. Thus, the design and implementation of a global registry is sorely needed in order to prospectively evaluate worldwide patterns of care and outcomes in patients with breast cancer. Components of this registry should include random selection of centers of variable practice settings in multiple countries and accurate and rapid data reporting at prestudy and follow-up timepoints. Data collected would include tumor and demographic factors, staging information, treatment rendered, and survival. Variables that influenced the treatment selected would be assessed. This unique international effort would allow the development of strategies to improve diagnostic and treatment-related standards of care and survival outcomes, thus reducing the breast cancer burden worldwide.

Breast Neoplasms↗
PubMed2003

Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer.

BACKGROUND: HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. METHODS: HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. RESULTS: HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P<.001; for PR, r = -0.24, P =.010. Cohort B [n = 188]: for ER, r = -0.39, P<.001; for PR, r = -0.26, P<.001). Among patients with HR-positive tumors, HER-2/neu-positive tumors had statistically significantly lower ER/PR levels than HER-2/neu-negative ones (Cohort A: for ER, median = 25 fmol/mg [interquartile range [IQR] = 13-78] versus median = 38.5 fmol/mg [IQR = 17-99] and P =.031; for PR, median = 35 fmol/mg [IQR = 12-119] versus median = 88.5 fmol/mg [IQR = 22-236] and P<.001. Cohort B: for ER, median = 44 fmol/mg [IQR = 13-156] versus median = 92 fmol/mg [IQR = 35-235] and P<.001; for PR, median = 36 fmol/mg [IQR = 13-108] versus median = 84 fmol/mg [IQR = 24-250] and P<.001). Patients with higher levels of HER-2/neu overexpression or amplification had statistically significantly lower levels of ER/PR than patients with lower levels of HER-2/neu overexpression or amplification. CONCLUSION: Because absolute HR levels are strongly related to response to hormone therapy in primary and advanced breast cancer, reduced ER/PR expression may be one mechanism to explain the relative resistance of HER-2/neu-positive:HR-positive tumors to hormone therapy.

Breast Neoplasms↗
PubMed2003

Platinum-taxane combinations in metastatic breast cancer: an evolving role in the era of molecularly targeted therapy.

Metastatic breast cancer is a partially chemotherapy-sensitive neoplasm. Docetaxel appears to be the most active single agent for this condition. The platinum coordination complexes are also active, but are seldom used. An emerging literature suggests that taxane-platinum combinations have substantial activity. Trastuzumab, a molecularly targeted therapy for metastatic breast cancer is active as a single agent in HER2-overexpressing disease, and has been demonstrated to augment the activity of other agents in random assignment trials. Preclinical data suggest a powerful synergistic interaction between trastuzumab and both platinum and docetaxel. In early trials, platinum-taxane-trastuzumab combinations have exhibited promising clinical activity. The potential for cardiac toxicity when trastuzumab is combined with the anthracyclines suggests a further rationale for the development of non-anthracycline regimens, especially in the adjuvant setting. Randomized, multicenter, phase III trials in the metastatic and adjuvant setting are currently underway to test the hypothesis that synergistic combinations of docetaxel, platinums, and trastuzumab will result in superior safety as well as efficacy.

Antibodies, Monoclonal↗
PubMed2002

A human ovarian carcinoma murine xenograft model useful for preclinical trials.

OBJECTIVE: To establish a murine xenograft model of human ovarian carcinoma. METHODS: A slurry of fresh human tumor from patients with intraperitoneal malignancies was heterotransplanted intraperitoneally into nude (nu/nu) and severely combined immunodeficient mice (CB-17, SCID). Xenograft growth was assessed by serial examination and necropsy. The xenografts were passaged to new animals when tumors were palpably greater than 1 cm(3). Histopathologic analysis of the xenografts was performed at each passage as well as immunohistochemical staining for p53 mutations. Persistent expression of human genes by the xenografts at higher passages was assessed by RT-PCR amplification of the human beta-globin gene. This xenograft model was used in the preclinical evaluation of an adenoviral vector containing a beta-galactosidase reporter gene and a wild-type p53 gene. RESULTS: Tumor growth was not established in any of the nude mice heterotransplanted with tissue from six different ovarian cancer patients. Eleven of 13 specimens established xenograft growth when injected in SCID mice. Nine xenografts have been subsequently passaged between 6 and 24 animal generations to date. All xenografts retained histopathologic similarities to their original human tumors and the p53 expression patterns remained stable through higher passages. Within 24 h after intraperitoneal administration of an adenoviral vector, transduction of the reporter gene was evident in the xenografts. In addition, administration of an adenoviral vector containing a wild-type p53 gene significantly decreased the tumor burden compared to controls (P < 0.04). CONCLUSIONS: This murine xenograft model of human ovarian carcinoma appears to be reliable and reproducible and has utility for the study of novel therapeutics.

Adenoviridae↗
PubMed2002

A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer.

PURPOSE: To determine the safety, gene transfer, host immune response, and pharmacokinetics of a replication-deficient adenovirus encoding human, recombinant, wild-type p53 (SCH 58500) delivered into the peritoneal cavity (i.p.) alone and sequentially in combination with platinum-based chemotherapy, of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer containing aberrant or mutant p53. METHODS: SCH 58500 was administered i.p. to three groups of patients with heavily pretreated recurrent disease. Group 1 (n=17) received a single dose of SCH 58500 escalated from 7.5 x 10(10) to 7.5 x 10(12) particles. Group 2 (n=9) received two or three doses of SCH 58500 given alone for one cycle, and then with chemotherapy for two cycles. The SCH 58500 dose was further escalated to 2.5 x 10(13) particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5 x 10(13) particles/dose per day i.p. alone for cycle 1 and then with intravenous carboplatin/paclitaxel chemotherapy for cycles 2 and 3. RESULTS: No dose-limiting toxicity resulted from the delivery of 236/287 (82.2%) planned doses of SCH 58500. Fever, hypotension abdominal complaints, nausea, and vomiting were the most common adverse events. Vector-specific transgene expression in tumor was documented by RT-PCR in cells from both ascitic fluid and tissue biopsies. Despite marked increases in serum adenoviral antibody titers, transgene expression was measurable in 17 of 20 samples obtained after two or three cycles of SCH 58500. Vector was detectable in peritoneal fluid by 24 hours and persisted for as long as 7 days whereas none was detected in urine or stool. There was poor correlation between CT scans and CA125 responses. CA125 responses, defined as a greater than 50% decrement in serum CA125 from baseline, were documented in 8 of 16 women who completed three cycles of the multidose regimen. CONCLUSION: CT scans are not a valid measure of response to i.p. SCH 58500 due to extensive adenoviral-induced inflammatory changes. Intraperitoneal SCH 58500 is safe, well tolerated, and combined with platinum-based chemotherapy can be associated with a significant reduction of serum CA125 in heavily pretreated patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.

Adenoviridae↗
PubMed2002

Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500.

OBJECTIVE: We have previously reported the safety, efficient gene transfer, and favorable CA125 responses of individuals with recurrent ovarian cancer treated by p53 gene replacement with the adenoviral vector SCH 58500. The purpose of the present investigation was to evaluate the long-term follow-up of these heavily pretreated patients subsequent to SCH 58500 dosing. METHODS: Patients (n=36) were treated with either single-dose SCH 58500 in the phase I study or with multiple doses (MD) of SCH 58500 over multiple cycles in combination of platinum-based chemotherapy in the phase I/II portion of the study. Five patients were initially treated in the single-dose group and re-enrolled in the MD group. The MD group was evaluated both without the re-enrolled patients as MD1 (n=19), and as MD2 (n=24), which included them. Patients who were only treated on the single-dose arm were designated as SD (n=12). Most patients received additional chemotherapy at the discretion of their physicians on completion of the trial. The current analysis is a retrospective sequential cohort survival analysis. RESULTS: The first patient was treated in March 1997 and the last patient completed SCH 58500 in September 1998. There was no difference in age at diagnosis, Karnofsky performance status, interval between diagnosis to SCH 58500, prior cycles or regimen of chemotherapy, platinum-free interval, percent platinum refractory patients, pretreatment CA125, or largest tumor volume between groups. Both MD groups had a slightly longer chemotherapy-free interval before SCH 58500 than the SD group. Median survival of individuals who received MD SCH 58500 with chemotherapy was 12-13.0 months, compared to only 5 months for those treated with SD SCH 58500. There are 10 long-term survivors more than 20 months after MD treatment for recurrent disease compared to only 2 long-term survivors after SD SCH 58500. CONCLUSION: The 12- to 13.0-month median survival in a heavily pretreated population with recurrent ovarian cancer compares favorably to the 16-month median survival for individuals treated with paclitaxel at the time of initial recurrence of this disease and is more than double the 5-month survival seen with palliative radiotherapy or paclitaxel failure. These data suggest that further study of SCH58500 is clearly indicated.

Adenoviridae↗
PubMed2002

Nucleoside transport inhibitors, dipyridamole and p-nitrobenzylthioinosine, selectively potentiate the antitumor activity of NB1011.

NB1011, a novel anticancer agent, targets tumor cells expressing high levels of thymidylate synthase (TS). NB1011 is converted intracellularly to bromovinyldeoxyuridine monophosphate (BVdUMP) which competes with the natural substrate, deoxyuridine monophosphate, for binding to TS. Unlike inhibitors, NB1011 becomes a reversible substrate for TS catalysis. Thus, TS retains activity and converts BVdUMP into cytotoxic product(s). In vitro cytotoxicity studies demonstrate NB1011's preferential activity against tumor cells expressing elevated TS protein levels. Additionally, NB1011 has antitumor activity in vivo. To identify drugs which interact synergistically with NB1011, we screened 13 combinations of chemotherapeutic agents with NB1011 in human tumor and normal cells. Dipyridamole and p-nitrobenzylthioinosine (NBMPR), potent inhibitors of equilibrative nucleoside transport, synergized with NB1011 selectively against 5-fluorouracil (5-FU)-resistant H630R10 colon carcinoma cells [combination index (CI)=0.75 and 0.35] and Tomudex-resistant MCF7TDX breast carcinoma cells (CI=0.51 and 0.57), both TS overexpressing cell lines. These agents produced no synergy with NB1011 in Det551 and CCD18co normal cells (CI > 1.1) lacking TS overexpression. Dipyridamole potentiated NB1011's cytotoxicity in medium lacking nucleosides and bases, suggesting a non-salvage-dependent mechanism. We demonstrate that nucleoside transport inhibitors, dipyridamole and NBMPR, show promise for clinically efficacious combination with NB1011.

Antimetabolites, Antineoplastic↗
PubMed2002

Inhibition of cell growth by NB1011 requires high thymidylate synthase levels and correlates with p53, p21, bax, and GADD45 induction.

NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel small molecule anticancer agent. NB1011 is selectively active against tumor cells expressing high levels of thymidylate synthase (TS), a critical enzyme in DNA biosynthesis. NB1011 is different from the current TS-targeted drugs, which require inhibition of TS to be effective, because NB1011 cytotoxicity depends upon activation by TS. Here we report a dose-dependent, antitumor activity of NB1011 against established Tomudex-resistant breast cancer (MCF7TDX) xenografts in athymic mice. Against 5-fluorouracil-resistant colon carcinoma (H630R10) xenografts, NB1011 was as efficacious as irinotecan, a drug recently approved for the treatment of 5-fluorouracil-resistant colon cancer. To gain insight into the mechanisms NB1011 uses to suppress cellular growth, we analyzed the downstream molecular events in the high TS-expressing MCF7TDX and RKOTDX cell lines upon NB1011 treatment. NB1011 treatment increased the mRNA levels of p21, Bax, and GADD45. Furthermore, NB1011 induced p53, p21, and Bax proteins specifically in high TS-expressing tumor cells, whereas no induction was observed in low TS-expressing tumor cells (MCF7) or normal cells (WI38). Cell cycle analysis demonstrated that NB1011 treatment of MCF7TDX and RKOTDX cells resulted in an accumulation of cells in the G2-M phase of the cell cycle. Altogether, our data indicate that the induction of the p53 target genes p21, bax, and GADD45, with a concomitant deregulation of the cell cycle, may represent one of the mechanisms by which NB1011 exerts its growth-suppressive effects.

Animals↗