Hakan Cam

Nationwide Children's Hospital · Center for Childhood Cancer and Blood Diseases

Antibodies targeting IGF-1R induce objective responses in only 5-15% of children with sarcoma. Understanding mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R-targeted antibodies. Sensitivity to the IGF1R-targeting antibody TZ-1 was determined in rhabdomyosarcoma (RMS) and Ewing sarcoma (EWS) cell lines. A...

The pre-metastatic niche (PMN) represents an abnormal microenvironment devoid of cancer cells, but favoring tumor growth. Little is known about the mechanisms that generate the PMN or their effects on host cells within metastasis-prone organs. Here, we investigated by using spontaneous metastatic models whether lung epithelial cells are essential f...

Background: Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isofor...

The authors have withdrawn the journal submission associated with this preprint and requested that the preprint also be withdrawn.

Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant e...

Background: The pre-metastatic niche (PMN) represents an abnormal microenvironment devoid of cancer cells, but favoring tumor growth. Little is known about the mechanisms that generate the PMN or their effects on host cells within metastasis-prone organs. Osteosarcoma is a malignant tumor of bone made devastating through aggressive metastatic sprea...

Osteosarcoma (OS) kills patients through aggressive metastatic spread, primarily to lung tissues. Our lab has sought to understand that tumor-host interactions that mediate this propensity for OS cells to colonize and grow in the lung. We identified two factors, IL6 and CXCL8, that become overexpressed in metastatic OS nodules relative to the same...

Osteosarcoma (OS), a malignant tumor of bone, kills through aggressive metastatic spread almost exclusively to the lung. Mechanisms driving this tropism for lung tissue remain unknown, though likely invoke specific interactions between tumor cells and other cells within the lung metastatic niche. Aberrant overexpression of ΔNp63 in OS cells directl...

Osteosarcoma (OS) kills patients through aggressive metastatic spread, primarily to lung tissues. Our lab has sought to understand the tumor-host interactions that facilitate growth of OS cells specifically within the lung. We previously identified two intercellular signaling molecules, IL6 and CXCL8, which exhibit enhanced expression when primary...

Background STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5. Methods and findings An in silico fragment-based dru...

Kinomescan results for LY5. LY5 exhibits no interactions sterically or allosterically to the active sites of 96 protein or lipid kinases at 1 μM LY5 (A), mapped S-Score (35) = 0. At 5 μM LY5 (B), only interaction with PLK3 was identified, mapped S-score (35) = 0.01. (PDF)

Non-compartmental PK parameters. Comparison of maximum drug concentration (Cmax), time at Cmax (Tmax) drug exposure (AUC), and oral bioavailability (F) of LY5 in mice (n = 10 for IV, PO, and IP routes) (A) and two study dogs (B and C). (PDF)

LY5 does not enhance the effects on cell viability in cells without STAT3 expression. (A) ES cell line ES-3 was transfected with either negative control siRNA (NC siRNA) or STAT3-targeting siRNA #7. After 72 hrs of transfection, cells were harvested and analyzed for total (T) STAT3 and GAPDH protein expression by immunoblotting. (B) RH30, ES-3, ES-...

p63 is a structural homolog within the 53 family encoding two isoforms, ΔNp63 and TAp63. The oncogenic activity of ΔNp63 has been demonstrated in multiple cancers, however the underlying mechanisms that contribute to tumorigenesis are poorly characterized. Osteosarcoma (OSA) is the most common primary bone tumor in dogs, exhibiting clinical behavio...

s: AACR Special Conference: Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; November 3-6, 2013; San Diego, CA For patients with most types of solid tumors, metastases drive the morbidity and mortality of their disease. For patients with osteosarcoma this is particularly true, with metastases that occur almost excl...

Under conditions of DNA damage, the mammalian target of rapamycin complex 1 (mTORC1) is inhibited, preventing cell cycle progression and conserving cellular energy by suppressing translation. We show that suppression of mTORC1 signaling to 4E-BP1 requires the coordinated activity of two tumor suppressors, p53 and p63. In contrast, suppression of S6...

The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63 which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63- and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors...

Background: The tumor suppressor gene p63 and its family members p53/p73 have been described as critical determinants of tumorigenesis. ΔNp63, a splice variant of p63 lacking the N-terminal transactivation domain, is thought to antagonize the transcriptional regulation of the p53, p63 and p73 target genes and blocks their tumor suppressor activity....

Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA damaging agents, however the molecular mechanism is not well understood. We found that an mTOR...

Background: The p53 families of transcription factors (p53, p63, and p73) are known to be involved in cell stress response, development and tumor suppression. It has been shown that multiple splicing sites and alternative promoter regions lead to each of these proteins having multiple isoforms. The TA isoforms, which contain the transactivation dom...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Oncogenic signaling leads to DNA replication stress, DNA damage and consequently DNA damage response (DDR), a barrier for tumorigenesis. For survival and proliferation, cancer cells must overcome this oncogene-induced DDR, but the molecular mechanism by which this is ach...

Integration of cellular and extracellular signals maintains tissue homeostasis under conditions of normal proliferation and stress. A central player in regulating responses to stress is the serine/threonine kinase mammalian target of rapamycin (mTOR). In many cancers, mTOR complex 1 (mTORC1) signaling is enhanced, even under conditions where such s...

The mTOR complex-1 (mTORC1) coordinates cell growth and metabolism, acting as a restriction point under stress conditions such as low oxygen tension (hypoxia). Hypoxia suppresses mTORC1 signaling. However, the signals by which hypoxia suppresses mTORC1 are only partially understood, and a direct link between hypoxia-driven physiological stress and...

Krebserkrankungen zeichnen sich häufig durch Störungen zellulärer Differenzierungsprozesse aus. So weisen Rhabdomyosarkome, die aus Muskelvorläuferzellen hervorgehen, Differenzierungsdefekte auf, die zur unkontrollierten Proliferation der Tumorzellen führen. Bislang ist ungeklärt, ob die Differenzierungsdefekte auf der verstärkten Expression von In...

The p53 family comprises the tumor suppressor p53 and the structural homologs p63 and p73. How the three family members cooperate in tumor suppression remains unclear. Here, we report different but complementary functions of the individual members for regulating retinoblastoma protein (RB) function during myogenic differentiation. Whereas p53 trans...

Efficient expression of genes transferred by retroviral vectors is a prerequisite for gene therapy, especially when the biological effect depends on the amount of transgene product. High-level gene expression is desirable for several gene therapy approaches involving T lymphocytes. We evaluated standard retroviral vectors with cis-regulatory contro...