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Previous Projects

Therapeutic platform for radiation-induced invasive brain tumor

(放射治療後周邊浸潤小島腫瘤微環境之研究與治療)

2013/08/01 ~ 2016/07/31

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High grade gliomas (WHO grade III-IV) are the most frequent and common type of malignant brain tumors in adults and persist as serious clinical problems. Unlike the remarkable improvement in survival rate of breast cancer, melanoma, and prostate cancer, the curing rate of high grade glioma remains poor and barely improves in last 10 years.  Although patient's survival rate depends on the histological grade of the tumor, glioma cell invasion into adjacent normal brain regions, so called invasion tumor front or infiltration islands, is believed to be the major reason for the failure of these tumors to treatments including neurosurgery, radiation therapy (RT), and chemotherapy.  To understand the behaviors of tumor invasion and target the invasion by new form therapies becomes very important in treating high-grade gliomas. A suitable pre-clinical animal brain tumor model is thus required.  PI’s lab has recently established a new murine astrocytoma tumor model, ALTS1C1.  The ALTS1C1 cells have been proved to be a good brain tumor model similar to human brain tumor and to fit into these purposes.  Using this murine tumor model, we have demonstrated that primary tumor core and invasion tumor front have different tumor microenvironments. Furthermore, our recent preliminary data showed that conventional radiation therapy (RT) reduces the tumor burden of primary tumor core as anticipated, but as compared to control tumors, tumor invasiveness and angiogenesis are enhanced in the invasion tumor front and infiltration islands.  These results are same as the failure pattern when high-dose RT was given in human brain tumor.  In this project, we aim to investigate factors that are associated with distinct tumor microenvironment in the invasion tumor front of ALTS1C1 tumors and contribute to the distinct response to RT.  The factors identified in the invasion tumor front can provide information for designing new therapeutic protocol to enhance RT effects.  To achieve this goal, three specific aims are proposed.  They are:

(1)  To establish a pre-clinical invasive brain tumor model for the research aiming on designing therapeutic strategy against invasive brain tumor.

(2)  To explore the effects of radiation therapy alone or concomitant with TMZ therapy on the microenvironments of invasion tumor front.

(3)  To develop a multiple therapeutic platforms using bone marrow-derived monocytes as cellular carrier to deliver therapeutic nanoparticles as adjuvant therapy.

Throughout this study, we anticipates establishing a therapeutic platform to target RT-induced invasive brain tumors and providing a new therapeutic protocol for the treatment of high grade glioma.

 

Key words: glioma, radiation therapy, tumor microenvironment

Double faces of NO-polarized M2 TAMs in recurrent tumors

(探討一氧化氮極化的M2型腫瘤巨嗜細胞在復發腫瘤中的雙重特性)

 2012/01/01 ~ 2014/12/31

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NO produced by M1 tumor-associated macrophages (TAMs) is a critical mediator for the cytotoxic activity of TAMs against cancer cells.  Conversely, NO produced by M2 TAMs could promote tumor progression. The local concentration of NO was frequently used to explain this biphasic nature of NO, but the threshold concentration has never been determined. In my current NHRI IRG (2009/1/1 ~ 2011/12/31), entitled “TAMs: target and vector in cancer radiotherapy”, we found that the inhibition of NO production by NOS inhibitor, L-NAME, could enhance the efficacy of radiation therapy (RT), but diminish the therapeutic effect of IL-3-mediated prodrug therapy.  Using two treatment protocols, RT and tk/GCV therapy, we found that both therapies could cause non-iNOS expressing M2 TAMs to express iNOS, but they have different effects on tumor growth.  This indicates that the effect of NO on TAMs is not only dependent on local concentration, but also nearby microenvironmental context.  The complexity of the NO signaling pathway and its dependence on environmental context gives us pause before concluding that the inhibition of NO production by TAMs is a promising therapeutic strategy for all tumors or therapies.  Thus, a more thorough molecular understanding of NO signaling in TAMs and tumor microenvironments after different therapies with divergent responses to NO-associated therapies is necessary. In this renewal grant, we aim to examine the hypothesis that different microenvironments resulted from different treatment protocols or different types of tumors can influence the effects of NO-polarized M2 TAMs on tumor growth.  The success of this study will be the first to demonstrate that the opposite role of NO on tumor growth depends on the environmental factors nearby TAMs.  To achieve this goal, three specific aims are proposed.

(1)  To illustrate the molecular signaling pathways of NO on TAMs function.

(2)  To identify effective factors that are responsible for the opposite effects of NO-polarized M2 TAMs in recurrent tumors of tk/GCV therapy.

(3)  To verify whether the roles of NO-polarized M2 TAMs in recurrent prostate tumors also occur in glioma.

Development of stimulus-responsive polymersomes, polymer bubblesomes and Au/organic hybrid nanoparticles for ultrasound- and macrophages-mediated cancer therapy

( 發展仿生性多分子自組裝聚合體與奈米金顆粒作為超音波與巨嗜細胞主導的腫瘤治療藥劑)

2010/08/01 ~ 2013/07/31

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The microenvironments of tumor are heterogeneous (such as the difference of oxygen concentration), both spatially and temporally, and can change in response to many forms of cytotoxic therapy. This has made tumor as one of the most complex diseases to be cured. Development of new novel agent against heterogeneous tumor microenvironments is demanded. An effective therapeutic agent requires not only have good cytotoxicity, but also (1) specific targeting, (2) maximum concentration, (3) guidable, and (4) responsive to microenvironmental changes. The overall aim of this project is to develop Au/organic hybrid nanoparticles as the agent for photo dynamic therapy (PDT) (subproject 1) and stimulus-responsive polymer vesicles and bubblesomes as carriers for therapeutic anticancer and ultrasound (bubble) contrast agents (subproject 2). The polymersomes and nanoparticles will be specifically delivered to tumor sites or specific hypoxia regions by tumor specific aptamer or antibody (subprojects 1 and 2) or hypoxia tropism macrophages (HTM) (subproject 4), respectively. After the maximum therapeutic agent reaches the target, which can be monitored by ultrasound imaging system (subproject 3), the therapeutic agent can be either released by the unique properties of tumor microenvironment (e.g. low pH), (subproject 2) or trigger by ultrasound (subproject 3). This proposal integrates the intelligence of two Chemists (subprojects 1 and 2) to develop gold nanoparticles, stimulus-responsive polymersomes, and targeting devices, one Physicist (subproject 3) to develop Ultrasound system, and one Biologist (subproject 4) to derive HTM as biological delivery system to target the area that most therapeutic drugs can’t reach, namely hypoxia region. We believe that this approach has not been intended before and will be a big challenge and hope for current research aiming on targeting malignant tumors. The success of this project not only paves a new pathway for cancer therapy, but also enhances the development and medical application of polymersomes, nanoparticles, ultrasound, and macrophages.

        The most challenge of this project is how to integrate 3 systems into one. For example, it is feasible to develop pH responsive polymersomes as demonstrated by the recent publication of one of the PI, Prof. Chiu. It is also feasible to make a targeting microbubble for ultrasound imaging and therapy. However, to make a polymer bubblesomes to include microbubbles and therapeutic drug within a polymersome has not been reported before. Our ambition is actually larger to have HTM as biological delivery system for these polymersomes and test them in a pre-clinical prostate tumor model.

Key words: stimulus-responsive polymersomes, Au/organic hybrid nanoparticles, ultrasound imaging, tumor-associated macrophages, prostate cancer

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