Evolving Approaches

As the underlying mechanisms of oncogenic transformation are deciphered with increasing speed and the general knowledge of biological processes is steadily expanding, new approaches to fight cancer emerge. These attempts are based either on disrupting aberrant signaling in the tumor cell or enhancing processes enabling the eradication of tumors.

In most cancers the mechanisms of apoptosis, i.e., programmed cell death, are dysregulated; many tumor cells have an altered threshold, but are still able to undergo apoptosis. Therefore, direct induction of programmed cell death is believed to be a powerful strategy to treat cancer. Apoptosis can be initiated by triggering of death receptors through extrinsic factors like FasL (CD95L), tumor necrosis factor-related apopto-sis-inducing ligand (TRAIL) or TNF. To this end, the feasibility of Fas ligation for cancer therapy has been demonstrated (Shimizu et al. 1996). However, systemic treatment with Fas agonists such as anti-Fas antibodies or multimeric recombinant FasL causes severe systemic toxicities (Timmer et al. 2002). To overcome this problem, Samel and colleagues targeted soluble FasL (sFasL) to the tumor using a tumor specific single chain antibody; upon binding to the respective cell surface molecule, these constructs aggregate, thereby mimicking the affect of membrane bound FasL (Samel et al. 2003). Treatment with this antibody-sFasL fusion protein did not cause any systemic toxicity, but prevented tumor growth in a xenogeneic tumor model. Analogously, a single chain antibody-sTRAIL fusion protein with specificities for either CD7 (Bremer et al. 2005a) or the EGFR (Bremer et al. 2005b) demonstrated preclinical efficacy. This approach offers the advantage that cancer cells are more sensitive to TRAIL-induced apo-ptosis than normal cells. Interestingly, targeting sTRAIL to antigen expressing tumor cells not only induced apoptosis in those, but also in antigen-negative bystander cells (Bremer et al. 2005b).

Another method to directly harm the tumor cells is to interfere with the translation of messenger RNA and thereby to block the expression of proteins. This can be achieved by the use of antisense RNA, ribozymes, RNA interference or more broadly by RNases. RNA-based strategies hold the potential for exquisite selectivity; nuclease sensitivity, rapid plasma elimination and poor intracellular delivery, however, hamper their use as therapeutic agents. These problems have already been addressed by use of carriers and chemical modifications, thereby substantially prolonging their circulation lifetime. Selective delivery of these agents was achieved by their fusion to targeting devices such as mAbs and specific ligands. For instance, tumor targeting of chemically modified antisense oligonucleotides specific for c-myc (Ou et al. 2005) or antisense oligonucleotides specific for c-myb was increased by encapsulation within liposomes (Brignole et al. 2005). Short interfering (si)RNA - similar to antisense oligonucleotides - specifically silences gene expression. Since siR-

NA approaches are both efficient and robust, this technology has become a frequently used tool for specific gene silencing in vitro. Consequently, siRNA are now being seized upon as drug candidates but face the same problems as antisense oligonucleotides, i.e., poor stability, short elimination half-life and inefficient mechanisms for delivery of siRNA to respective cells. One way to deliver siRNA to tumor cells is by ligand-targeted nanoparticles (Schiffelers et al. 2004): such constructs demonstrated tumor selectivity as well as specific silencing of the targeted gene both in vitro and in vivo in preclinical models. Nevertheless, delivery of siRNA both with respect to specificity and efficacy remains to be improved prior to translation into clinical trials.

Targeting either costimulatory or immunmodulato-ry molecules to the tumor microenvironment should enhance naturally occurring immune processes. In the early 1990s a large series of reports demonstrated that triggering of costimulatory pathways augments the initiation and/or efficacy of immune responses against the tumor; hence, it was conceived that aiming costimula-tory molecules to the cell surface of tumors renders them immunogenic. Recombinant fusion proteins containing the costimulatory molecule B7 were able to mediate anti-tumor effects if directed to the tumor (Moro et al. 1999). Grosse-Hovest and colleagues improved this approach by generating a bispecific Ab which allowed the targeting of an anti-CD28 Ab to melanoma cells (Grosse-Hovest et al. 2003). This bispecific antibody mediated effective tumor eradication by activation of non-specific cytotoxic cells. The therapeutic potential of several other bispecific diabodies is currently being tested in vitro and in vivo in preclinical models. Diabodies specific for CD19 and CD3 or CD19 and CD16 mediated lysis of tumor cells by T cells or mononuclear cells, respectively (Bruenke et al. 2005) (Fig. 15.4). Interestingly, a synergistic anti-tumor effect of anti-CD19/CD3 and anti-CD19/CD16 diabodies was obvious in a murine non-Hodgkin's lymphoma model (Kipriyanovet al. 2002). Furthermore, anti-p-glycopro-tein/CD3 diabodies in combination with activated PBLs inhibited the growth of xenograft tumors expressing p-glycoprotein (Gao et al. 2004). The use of multivalent antibodies is likely to further improve this strategy; a trispecific Ab targeting simultaneously CD3 and CD28 and the tumor abolished the requirement of pre-activated T cells for tumor lysis (Wang et al. 2004).

Fig. 15.4. Mode of action of immune modulating or apoptosis inducing antibody fusion proteins. Bispecific antibody fragments allow the targeting of immunomodulatory molecules to the tumor cell. As exemplified, anti-CD16/CD19 diabody or anti-CD19/CD3 bispecific scFv can enhance the NK-cell or T-cell response, respectively, to B-cell lymphomas. Triggering of death receptors by targeting extrinsic factors such as FasL or TRAIL to the cell surface of tumor cells can induce apoptosis in an autocrine as well as a paracrine way

Fig. 15.4. Mode of action of immune modulating or apoptosis inducing antibody fusion proteins. Bispecific antibody fragments allow the targeting of immunomodulatory molecules to the tumor cell. As exemplified, anti-CD16/CD19 diabody or anti-CD19/CD3 bispecific scFv can enhance the NK-cell or T-cell response, respectively, to B-cell lymphomas. Triggering of death receptors by targeting extrinsic factors such as FasL or TRAIL to the cell surface of tumor cells can induce apoptosis in an autocrine as well as a paracrine way

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10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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