EDITOR'S PICK: Antitumor effects are enhanced by inhibiting 2 pathways rather than 1
Two independent research groups have found that simultaneous inhibition of two signaling pathways resulted in substantially enhanced antitumor effects in mouse models of prostate and breast cancer. In an accompany commentary, Steven Grant, at Virginia Commonwealth University Health Science Center, Richmond, discusses the clinical importance of these studies and highlights some of the questions that still need to be answered.
In the first study, Pier Paolo Pandolfi and colleagues, at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and Memorial Sloan-Kettering Cancer Center, New York, report that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with a drug that inhibits the mTOR signaling pathway showed increased activation of the MAPK signaling pathway. Similar results were observed in a mouse model of prostate cancer following treatment with the same drug. As inhibition of the MAPK signaling pathway enhanced the antitumoral effects of inhibition of the mTOR signaling pathway in mice transplanted with a human breast cancer cell line, the authors suggest that a combination therapy using drugs that target each pathway might improve the treatment of human cancers.
In the second study, Cory Abate-Shen and colleagues, at Columbia University College of Physicians and Surgeons, New York, and the University of Medicine & Dentistry of New Jersey, Piscataway, show that simultaneous inhibition of the mTOR and MAPK signaling pathways inhibited the in vitro growth of prostate cancer cell lines and the in vivo growth of prostate tumors in a mouse model of prostate cancer. This was particularly true in a model of highly aggressive and frequently lethal forms of the disease, which do not respond to hormone deprivation therapy, leading the authors to suggest that this combination therapy might be particularly useful for treating patients with advanced, hormone-refractory prostate cancer.
TITLE: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
Pier Paolo Pandolfi
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 667-2901; Fax: (617) 667-0610; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34739
TITLE: Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 851-4731; Fax: (212) 851-4572; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34764
TITLE: Cotargeting survival signaling pathways in cancer
Virginia Commonwealth University Health Science Center, Richmond, Virginia, USA.
Phone: (804) 828-5211; Fax: (804) 828-2174; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36898
HEMATOLOGY: Molecular insight into one form of the bleeding disorder von Willebrand disease
Individuals with von Willebrand disease (vWD) are at increased risk of bleeding compared with healthy individuals, for example, they tend to bruise more easily and suffer more nosebleeds and bleeding gums. There are four types of inherited vWD, and type 2B vWD is caused by genetic mutations that result in the generation of mutant forms of the protein vWF that differ from normal vWF in a region of the protein known as the A1 domain. A team of researchers at Georgia Institute of Technology, Atlanta, and Oklahoma Medical Research Foundation, Oklahoma City, has now characterized in great molecular detail how the function of mutant forms of vWF found in individuals with type 2B vWD and normal vWF differ, providing insight into why these mutant proteins cause an increased risk of bleeding. In an accompanying commentary, Michael Berndt, at the University College Cork, Ireland, and Robert Andrews, at Monash University, Australia, discuss the importance of these results.
TITLE: Platelet glycoprotein Ib-alpha forms catch bonds with human WT vWF but not with type 2B von Villebrand disease vWF
Georgia Institute of Technology, Atlanta, Georgia, USA.
Phone: (404) 894-3269; Fax: (404) 385-1397; E-mail: firstname.lastname@example.org.
Roger P. McEver
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Phone (405) 271-6480; (405) 271-3137; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35754
TITLE: Platelet adhesion: a game of catch and release
Michael C. Berndt
University College Cork, Cork, Republic of Ireland.
Phone: 353-21-4901616; Fax: 353-21-4901549; E-mail: M.Berndt@ucc.ie.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36883
HEMATOLOGY: Insight into the physiologic role of the blood protein Factor XII finally revealed
The formation of a blood clot is the culmination of a series of events that involve a number of proteins in the bloodstream, including Factor XI, which is one of the proteins activated early on in this cascade of events. Surprisingly, Factor XI is activated in different ways in the body and in a glass test tube. In a glass test tube, Factor XI is activated by a protein known as Factor XII, which is itself activated when it comes into contact with the glass. However, Factor XII plays no role in Factor XI activation in the body and its physiologic function and mechanism of activation have not been determined.
New data, generated by Martijn Gebbink and colleagues, at the University Medical Center Utrecht, The Netherlands, have identified the aggregates of misfolded proteins present in the blood of individuals with systemic amyloidosis (a disease in which misfolded blood proteins are abnormally deposited in organs and/or tissues, causing disease) as activators of Factor XII. Interestingly, activation of Factor XII by isolated misfolded proteins and misfolded proteins in the blood of individuals with systemic amyloidosis did not trigger the cascade of events that lead to blood clot formation. Rather, it triggered another series of events known as the kallikrein-kinin system, which influences the inflammatory response. In an accompanying commentary, Alvin Schmaier, at Case Western Reserve University, Cleveland, discusses these results in the context of previously published data.
TITLE: Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation
Martijn F.B.G. Gebbink
University Medical Center Utrecht, Utrecht, The Netherlands.
Phone: 31887557769; Fax: 31-887555418; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35424
TITLE: The elusive physiologic role of Factor XII
Alvin H. Schmaier
Case Western Reserve University, Cleveland, Ohio, USA.
Phone: (216) 368-1172; Fax: (216) 368-3014; E-mail: Schmaier@case.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36617
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