Historically, there have been major problems with the paradigm for the treatment of metastatic cancer. These include poor discrimation of drugs between host and cancer tissues, limited knowledge of appropriate targets, and inability to select patients who are likely to respond. Current advances, especially the introduction of targeted agents into the clinical setting, allow these critical issues to be addressed. We propose that the Phase I trial, which is the cornerstone for drug development, should be designed to provide basic knowledge regarding target impact and selection, upon which further trials can be built. In this regard, it is critical to recognize that molecularly targeted compounds may behave in a way that is fundamentally dissimilar to cytotoxic chemotherapy. For instance, targeted agents may be cytostatic, rather than cytotoxic, and only patients who bear a specific protein capable of being modulated by the drug may respond. Thus, rather than utilizing the standard paradigm for Phase I development of chemotherapeutic agents that is based predominantly on determination of maximum tolerated dose (MTD), a more suitable paradigm involving surrogate markers and functional endpoints is crucial. We, therefore, hypothesize that integration of intermediate biologic endpoints, which reflect interaction with or functional impact on the target, will provide key information for determining optimal biologic dose (OBD), as well as the foundation for further study of biomarker identification of responsive patients in subsequent Phase II studies. With such an undertaking, there must be effective cooperation between clinical and laboratory investigators, in addition to experts in the field of molecular imaging, in order to evaluate the ability of targeted drugs to modulate, interact with, or inhibit specific molecular and biochemical targets. Such cooperation is found at the M.D. Anderson Cancer Center (MDACC), where great emphasis is placed on clinical and translational drug development, as evidenced by our tremendous infrastructure! and educational support for clinical trials research. Indeed, MDACC has extensive facilties and extremely experienced faculty and personnel for data management, quality control, regulatory oversight, specimen acquisition, patient care, and translational studies to identify pharmacodynamic and molecular biomarkers. The significance of our proposed research is that it should advance the development of new cancer therapeutics by providing the groundwork for elucidating how response correlates with target impact, hence laying the foundation for successful personalized cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01CA062461-19S1
Application #
8628936
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (O1))
Program Officer
Ivy, S Percy
Project Start
1994-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
19
Fiscal Year
2013
Total Cost
$594,425
Indirect Cost
$166,781
Name
University of Texas MD Anderson Cancer Center
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Hong, David S; Garrido-Laguna, Ignacio; Ekmekcioglu, Suhendan et al. (2014) Dual inhibition of the vascular endothelial growth factor pathway: a phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors. Cancer 120:2164-73
Liu, Xiaochun; Lorusso, Patricia; Mita, Monica et al. (2014) Incidence of mucositis in patients treated with temsirolimus-based regimens and correlation to treatment response. Oncologist 19:426-8
Naing, A; Lorusso, P; Fu, S et al. (2013) Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma. Br J Cancer 108:826-30
Janku, Filip; Wheler, Jennifer J; Hong, David S et al. (2013) Bevacizumab-based treatment in colorectal cancer with a NRAS Q61K mutation. Target Oncol 8:183-8
Abrams, Jeffrey S; Mooney, Margaret M; Zwiebel, James A et al. (2013) Implementation of timeline reforms speeds initiation of National Cancer Institute-sponsored trials. J Natl Cancer Inst 105:954-9
Davies, Michael A; Fox, Patricia S; Papadopoulos, Nicholas E et al. (2012) Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma. Clin Cancer Res 18:1120-8
Subbiah, Vivek; Slopis, John; Hong, David S et al. (2012) Treatment of patients with advanced neurofibromatosis type 2 with novel molecularly targeted therapies: from bench to bedside. J Clin Oncol 30:e64-8
Naing, Aung; LoRusso, Patricia; Fu, Siqing et al. (2012) Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors. Clin Cancer Res 18:2625-31
Subbiah, Vivek; Naing, Aung; Brown, Robert E et al. (2011) Targeted morphoproteomic profiling of Ewing's sarcoma treated with insulin-like growth factor 1 receptor (IGF1R) inhibitors: response/resistance signatures. PLoS One 6:e18424
Borthakur, Gautam; Kantarjian, Hagop; Ravandi, Farhad et al. (2011) Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica 96:62-8

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