Zhang B.,Beckman Research Institute |
Li M.,City of Hope Cancer Center |
McDonald T.,Beckman Research Institute |
Holyoake T.L.,University of Glasgow |
And 4 more authors.
Blood | Year: 2013
Tyrosine kinase inhibitors (TKIs) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stemcells (LSCs), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity inCML LSCs, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSCs from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSCs) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony-forming ability and engraftment potential in immunodeficient mice. We found that the N-cadherin receptor plays an important role inMSC-mediated protection of CML progenitors fromTKI.N-cadherin-mediated adhesion to MSCs was associated with increased cytoplasmic N-cadherin-β-catenin complex formation as well as enhanced b-catenin nuclear translocation and transcriptional activity. Increased exogenousWnt-mediated b-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-cadherin and the Wnt-β-catenin pathway in protecting CML LSCs during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSCs to TKI treatment and suggest new targets for treatment designed to eradicate residual LSCs in CML patients. © 2013 by The American Society of Hematology.
News Article | December 7, 2016
A new study published in the just-published "Oncotarget" peer-reviewed medical journal has concluded that “in the setting of previously treated, advanced pancreatic cancer, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test.” The study was conducted by a team of researchers and clinicians from Perthera, Inc., a precision medicine company based in McLean, VA, the Pancreatic Cancer Action Network (PanCAN), Lombardi Comprehensive Cancer Center of Georgetown University, Cedars-Sinai Medical Center, Ohio State University, City of Hope Cancer Center, Virginia Mason Medical Center, and the Sidney Kimmel Cancer Center at Thomas Jefferson University. The study is entitled "a pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic patients participating in the Know Your Tumor (KYT) Initiative." Know Your Tumor is a benchmark precision cancer therapy program of the Pancreatic Cancer Action Network that is executed by Perthera. The study asserted that “molecular profiling of the tumor itself should remain the gold standard,” or as approved by the FDA. Liquid biopsies can "go wrong" in a variety of ways: mainly because the tumor isn't dumping DNA into the blood, or because the detection assays aren't sensitive enough to detect the DNA when it is too low in abundance to see. The investigators assessed the ability of the circulating genomic information obtained from a blood sample of 34 consecutively screened pancreatic cancer patients with metastatic disease to accurately recapitulate the genomic information obtained by direct analysis of a tumor biopsy obtained from the same patient taken at the same time. They used the high frequency of KRAS mutation (~90%) in pancreatic cancer as a benchmark for comparison, and they found that KRAS mutations “were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies." Dr. Jonathan Brody, the last author on the study and Director of Surgical Research and Co-director of the Jefferson Pancreas, Biliary and Related Cancer Center and on the scientific advisory board at Perthera, cautioned that "the results of this study should give people some pause; we need to be very careful about the state of the liquid biopsy field right now." He said, "we need to be very circumspect- in this study, we detected DNA with KRAS mutations in only a third of the patients that you should see the genomic alteration, so what does it say about being able to reliably detect actionable alterations that doctors would use to make critical treatment decisions?” Dr. Michael Pishvaian, the first author of the study and Perthera’s CMO as well as the Director of the Phase I Clinical Program and Co-Director of the Ruesch Center Pancreatic Cancer Program at Georgetown University added that “there will be times when a tumor biopsy is unable to be performed due to medical issues, and then could a liquid biopsy be considered. Pishvaian says: “There are papers that show good but not perfect concordance between the genomic information in tumor samples and blood samples, and our study in pancreatic cancer reveals something different. Some of the disparate results from these studies come from differences in the clinical aspects of the patients studied, but ultimately if liquid biopsies are to be used routinely for precision medicine applications then the field needs more improvements.” In the meantime, Emanuel “Chip” Petricoin, PhD, Perthera’s Chief Science Officer said, “Central to Perthera’s medical philosophy is that the patient should have as extensive molecular profiling as relevant, and blood-based testing will be great to add to our arsenal of testing options as it becomes more reliable and sensitive. So, we are committed to implementing molecular profiling technologies that have the best evidence of impact to patients' precision cancer therapy outcome and we will be constantly monitoring the state of the field on this topic. As the liquid biopsy technologies and approaches improve and become more sensitive, then we can validate them and implement them." ABOUT PERTHERA, INC.: Perthera is a founder- and venture-backed precision medicine company based in McLean, VA, that has achieved more than 1,000 case histories since it was founded about five years ago, often working in an alliance with cancer advocacy agencies as well as hospitals, community oncology practices, and academia. In every patient instance, the Company seeks to become the precision medicine partner on their cancer care team, providing the widest, deepest, and most independent range of service possible.
Schultheiss T.E.,City of Hope Cancer Center
Advances in experimental medicine and biology | Year: 2012
Radiation myelopathy is a rare but devastating injury to the spinal cord that usually results from an excessive radiation dose. In this chapter, we discuss the traditional and current understandings of the pathogenesis of this injury. A distinction is made between radiation damage, which occurs at the subcellular level, and radiation injury, which occurs at the tissue and organ level in response to radiation damage. Recent findings regarding the amelioration and treatment of both radiation damage and radiation injury are explored. These studies are promising developments but, as always, there are attendant caveats.
Krishnan A.,City of Hope Cancer Center |
Forman S.J.,City of Hope Cancer Center
Current Opinion in Oncology | Year: 2010
Purpose of review: AIDS-related malignancies are an ongoing cause of mortality in individuals with HIV infection. In the HIV-negative setting, high-dose chemotherapy or stem cell transplantation is an option for patients with hematologic malignancies. Prior to the advent of effective HIV therapy, stem cell transplantation was not feasible for HIV-positive patients. The purpose of this article is to explore the transplant options for HIV-positive patients after widespread use of highly active antiretroviral therapy. Recent findings: Early autologous stem cell transplantation has studies had high relapse rates but they demonstrated that mobilization and engraftment of autologous stem cells were possible in AIDS patients. Recently, in less advanced AIDS lymphoma, autologous stem cell transplantation has resulted in low transplant-related mortality and durable remissions. In addition, case-control studies of HIV-positive versus HIV-negative lymphoma patients undergoing autologous stem cell transplantation have shown similar transplant-related mortality and overall survival. The feasibility of allogeneic stem cell transplantation in HIV-infected individuals is less tested. There are challenges of drug interactions between highly active antiretroviral therapy and immunosuppressive agents as well as the potential for higher infection rates. Summary: The potential future applications of autologous and allogeneic stem cell transplantation are the cure of the malignancy as well as the underlying HIV infection by either transplantation of naturally resistant or genetically modified stem cells. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Luu T.,City of Hope Cancer Center |
Chung C.,The Angeles Clinic and Research Institute |
Somlo G.,City of Hope Cancer Center
Oncologist | Year: 2011
Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Con-comitantly, in the absence of an effective targeted mono-therapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability. © AlphaMed Press.
Kirkpatrick J.P.,Duke University |
van der Kogel A.J.,Radboud University Nijmegen |
Schultheiss T.E.,City of Hope Cancer Center
International Journal of Radiation Oncology Biology Physics | Year: 2010
Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (α/β = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen. © 2010 Elsevier Inc. All rights reserved.
Tommasi S.,City of Hope Cancer Center |
Besaratinia A.,City of Hope Cancer Center |
Wilczynski S.P.,City of Hope Cancer Center |
Pfeifer G.P.,City of Hope Cancer Center
Oncogene | Year: 2011
Loss of RASSF1A leads to several mitotic abnormalities, including cytokinesis failure and tetraploidization. Uncontrolled proliferation of tetraploid cells is known to trigger genomic instability and tumor development and is normally prevented through activation of a p53-dependent tetraploidy checkpoint. RASSF1A is the most commonly silenced and p53 is the most frequently mutated tumor suppressor gene in human cancer. However, their mutual contribution to tumorigenesis has never been investigated in animal models. Here, we explore whether concomitant loss of RASSF1A and p53 will result in increased levels of aneuploidy, genomic instability and tumorigenesis. We have intercrossed Rassf1a-knockout mice with mice lacking the p53 gene and generated a combination of single- and compound-mutant animals. Rassf1a-/- p53-/- mice were viable and fertile and developed normally. However, these mice were remarkably tumor prone and succumbed to malignancies significantly faster than single-mutant littermates, with a median survival time of 136 days (versus 158 days in p53-/- mice, P=0.0207, and >600 days in Rassf1a -/- animals, P<0.0001). Rassf1a-null mice with one functional p53 allele displayed a more moderate, yet tumor-prone phenotype, characterized by increased tumor multiplicity as compared with single knockouts. On cell-cycle profiling and cytogenetic analysis, cells derived from Rassf1a-/- p53-/- mice exhibited several mitotic defects associated with high levels of tetraploidy/aneuploidy. Conversely, cells with a proficient p53 allele could better cope with the mitotic failures imposed by Rassf1a loss. Altogether, we provide the first experimental evidence for a pivotal role of Rassf1a as an early gatekeeper gene, whose loss of function deteriorates cellular fitness by enhancing tetraploidization. Concomitant loss of p53, which causes unrestrained propagation of tetraploids into aneuploid cells, further undermines genomic stability and accelerates tumorigenesis. © 2011 Macmillan Publishers Limited All rights reserved.
Nguyen L.H.,City of Hope Cancer Center
Advances in experimental medicine and biology | Year: 2012
Advancement of in vitro osteogenesis, or the production of bone, is a complex process that has significant clinical implications. Surgical intervention of several spinal disorders entails decompression of the spinal cord and nerves which can lead to subsequent biomechanical instability of the spine. Spinal arthrodesis (fusion) is often required to correct this instability and necessary to eliminate the resulting pathological motion of vertebral segments. Therefore, the achievement of proper spinal fusion, is a critical determinant of treatment efficacy. This chapter focuses on the molecular and cellular components that are involved in bone growth and healing. Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are the precursor cells essential for the formation of the five different types of bone cells: osteoprogenitor cells, osteoblasts, osteoclasts, osteocytes and lining cells. Similarly, endothelial progenitor cells (EPCs) differentiate into endothelial cells, which are essential in angiogenesis and neovascularization. MSCs tri-lineage potential (osteogenic, chondrogenic and adipogenic lineages) have made them the focus of most experimental approaches. Here, we describe their individual roles, as well as pose novel concepts on how their collective role may be the optimal strategy to improve upon in vitro osteogenesis and whether this could also be translated to improved bone formation in vivo. Further, we discuss the various molecular markers that are available for cell identification and the tissue engineering strategies that could replicate the osteoinductive, osteoconductive and osteoproductive milieuthat is available in autograft. Finally, we present a broad primer on the possible integration of cellular, molecular and tissue engineering strategies to improve osteogenesis and the future trends that may bring the promise seen in the laboratory to fruition in preclinical animal models.
Gahrton G.,Karolinska Institutet |
Krishnan A.,City of Hope Cancer Center
Expert Review of Hematology | Year: 2014
Allogeneic transplantation has the potential to cure subgroups of patients with multiple myeloma, but its role is controversial due to high transplant-related mortality. Therefore, myeloablative allogeneic transplantation has fallen out of favor. Allogeneic transplantation using reduced-intensity conditioning (RICallo) has lower transplant-related mortality and may be an option for subgroups of patients. Upfront tandem autologous/RICallo (auto/RICallo) was shown to be superior to single auto or tandem auto/auto in both progression-free and overall survival in two studies with long-term follow-up, while four similarly designed studies with shorter follow-up did not show a significant advantage. All studies included patients less than 70 years of age. No study has shown that the auto/RICallo approach is inferior to auto or auto/auto. There have been indications that poor-risk cytogenetics may be overcome by the auto/RICallo approach. Encouraging results have also been seen in treatment of relapsed patients. Small studies indicate that combining allogeneic transplant with new proteasome inhibitors and immunomodulatory drugs may further improve results. Prospective studies including these drugs for induction, conditioning and post-allogeneic transplant maintenance are warranted and planned. New cell therapies, such as with natural killer cells have shown encouraging results in experimental animals and should be tried in combination with allotransplantation. © Informa UK, Ltd.
Kim J.Y.,City of Hope Cancer Center |
Hofstetter W.L.,University of Texas M. D. Anderson Cancer Center
Seminars in Thoracic and Cardiovascular Surgery | Year: 2012
Neoadjuvant chemoradiation is the standard of care for locally advanced esophageal cancer. After completion of chemoradiotherapy, deciding which patients benefit from surgery remains a challenge. For patients who decide on surgery, the optimal timing is unknown. The complexity of these questions requires an individualized approach, taking into account the expertise of the surgeon, the condition of the patient, and the biology of the tumor. © 2012.