Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Targeting HIF-1 for cancer therapy

Researchers have been studying metastasis for more than 100 years, and only recently have we gained insight into the mechanisms by which metastatic cells arise from primary tumours and the reasons that certain tumour types tend to metastasize to specific organs. Stephen Paget's 1889 proposal that metastasis depends on cross-talk between selected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil') still holds forth today. It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis. How has this field developed over the past century, and what major breakthroughs are most likely to lead to effective therapeutic approaches?

https://www.nature.com/articles/nrc1098.pdf?proof=t

The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited

Cancer Metastasis: Building a Framework

The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.

/pdf/tumour-stem-cells-and-drug-resistance-210hrtgy2n.pdf

Tumour stem cells and drug resistance

Tumor Metastasis: Molecular Insights and Evolving Paradigms

Heat shock transcription factor 1 (HSF1) is the master regulator of the heat shock responses in eukaryotes. Upon exposure to a variety of stresses, HSF1 activates its target genes, subsequently activating the heat shock responses. Although not well understood, the functions of HSF1 are far beyond the classical induction of heat shock responses. Recent reports have shown that HSF1 plays an important role in cancer development. We investigated the role and mechanism of HSF1 in regulating oncogene-mediated dysregulated cellular metabolism and cell growth in cancer cells. We found that oncogene ErbB2-overexpressing cancer cells possessed significantly higher level of glycolysis when compared to ErbB2-low expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of HSF1 and two critical glycolysis-regulating molecules, lactate dehydrogenase A (LDH-A) and Hexokinase (HK). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation and DNA binding activity, and promoted the rate of HSF1 protein translation. HSF1 bound to the promoter of LDH-A and transcriptionally activated LDH-A. Meanwhile, the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. These results demonstrate that in cancer cells, ErbB2 promotes glycolysis and cell growth through HSF1-mediated upregulation of LDH-A. Trastuzumab (Herceptin) and Paclitaxel (Taxol) are important drugs in treatment of breast cancers when used alone or in combination with other chemotherapeutics. However, acquired resistance develops in most treated patients, necessitating alternate treatment strategies. Increased aerobic glycolysis is a hallmark of cancer and inhibition of glycolysis may offer a promising strategy to preferentially kill cancer cells. We investigated the antitumor effects of trastuzumab and Taxol in combination with glycolysis inhibitors in breast cancer. We found that trastuzumab inhibits glycolysis via downregulation of HSF1 and LDH-A in ErbB2-positive cancer cells, resulting in tumor growth inhibition. Moreover, increased glycolysis via HSF1 and LDH-A contributes to trastuzumab and Taxol resistance. Strikingly, we found that combining trastuzumab or Taxol with glycolysis inhibition synergistically inhibited both drug-sensitive and -resistant breast cancers in vitro and in vivo, due to more efficient inhibition of glycolysis. These results show how glycolysis inhibition can dramatically enhance the therapeutic efficacy of trastuzumab in ErbB2-positive breast cancers, potentially useful as a strategy to overcome trastuzumab resistance. This work was supported by NIH Grant RO1CA149646, The Vincent F. Kilborn, Jr. Cancer Research Foundation, and Radiumhospitalets Legater Project 334003. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3208. doi:1538-7445.AM2012-3208

Abstract 3208: Overcoming cancer therapeutic resistance by targeting dysregulated glucose metabolism

Die ausgepragte Regenerationsfahigkeit der Leber ist ein Prozes, der durch unbekannte Faktoren im Pfortaderblut ausgelost wird, in eine massive, kurz anhaltende Proliferationswelle mundet und einer prazisen zeitlichen Steuerung unterliegt.

Einfluß der Leberregeneration auf das biologische Verhalten menschlicher Tumormetastasen in der thymuslosen Nacktmaus

Background: Growth of breast cancer is dependent upon sustained angiogenesis, of which vascular endothelial growth factor (VEGF) is a major stimulant. Increased expression of VEGF in breast cancers is associated with poor prognosis and disease recurrence, and anti-angiogenic agents are being developed as potential new therapies. Motesanib is an oral inhibitor of VEGF receptors 1, 2 and 3, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). This study determined the effects of motesanib on the growth of human basal-like breast cancer cell lines in immunodeficient mice, alone and in combination with paclitaxel.Materials and Methods: Breast cancer cells BT-549 and GILM2 were injected into the mammary fatpad (MFP) of mice; HCC1187 cells were injected on the subcutaneous flank. Mice with established tumors (150-200 mm 3 ) received motesanib orally BID, at 7.5, 25 or 75 mg/kg for three weeks. Tumors were collected for analysis of blood vessels (CD-31 staining), viable tumor area, and for markers of proliferation (Ki67) and apoptosis (cleaved caspase-3). GILM2 cells were injected into the tibia of mice to model growth in bone; mice with GILM2 MFP or tibia tumors received motesanib (25 mg/kg BID) or paclitaxel (24 mg/kg Q4Dx5), or the combination. Intratibial GILM2 tumors expressing luciferase were monitored by bioluminescence and radiography to evaluate osteolysis. Analyses of tumor size were assessed by ANOVA, and immunohistochemical tests by Student9s t tests.Results: Motesanib produced dose-dependent inhibition of growth of BT-549, GILM2 and HCC1187 tumors. All doses of motesanib significantly inhibited the growth of BT-549 tumors (>55% inhibition, P 25mg/kg had smaller viable tissue areas (P Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5057.

The Anti-Tumor Effect of Motesanib in Pre-Clinical Models of Human Basal-Like Breast Cancer.

Unterdrückung von osteolytischen läsionen mit src-kinase-hemmern

The present invention include methods and compositions for treating bone-resorbing diseases or bone resorption related to a pathologic condition generally, including, but not limited to osteoporosis, arthritis, rheumatoid arthritis, cancer metastases to the bone, bone cancer, hypercalcemia, osteolytic lesions with orthopedic implants, Paget's disease, and bone loss associated with hyperparathyroidism. Representative cancers include, but are not limited to breast cancer, prostrate cancer, colon cancer, endometrial cancer, multiple myeloma, renal cell carcinoma, heck and neck cancers, and cervical carcinoma. Arthritic conditions include, but are not limited to adjuvant-, collagen-, bacterial- and antigen-induced arthritis, particularly rheumatoid arthritis.

Janet E. Price

Papers

Abstract 3208: Overcoming cancer therapeutic resistance by targeting dysregulated glucose metabolism

Einfluß der Leberregeneration auf das biologische Verhalten menschlicher Tumormetastasen in der thymuslosen Nacktmaus

The Anti-Tumor Effect of Motesanib in Pre-Clinical Models of Human Basal-Like Breast Cancer.

Unterdrückung von osteolytischen läsionen mit src-kinase-hemmern

SKI 606 as src kinase inhibitor for treating osteolytic lesions