Tumor-selective Agents Research Articles

Identification of Hepatocellular Carcinoma-Specific Targets for Imaging and Therapy

Despite advances in the diagnosis and treatment of hepatocellular carcinoma (HCC), there are no tumor-selective agents that are clinically approved in the US for this disease. Here, we aimed to identify and validate molecules that are overexpressed on HCC plasma membrane compared to normal tissues, which could be facilitate the design, engineering, and testing of tumor-selective imaging and therapeutic agents. We analyzed next-generation sequencing (NGS) public datasets (TCGA and TIGER-LC) and NCI single cell RNA-sequencing datasets to identify overexpressed plasma membrane molecules and aimed to validate these targets using immunohistochemical staining (IHC) of patient tissue microarrays (TMAs), and flow cytometry using liver cancer cell lines (Huh7, HepG2, and Hep3B). NGS data identified GPC3, EGFR, MET, MUC13, and ROBO1 molecules overexpressed in HCC relative to non-tumor tissues. In HepG2 cell line, EGFR (p<0.05) and MET (p<0.01) demonstrated statistically significant increased median fluorescence intensity (MFI) relative to controls in flow cytometry. In the Hep3B cell line, MET, GPC3, and EGFR demonstrated an increased MFI relative to the control (p<0.01). No statistically significant difference was observed in Huh7 cell lines. IHC staining of TMAs for GPC3, MET, MUC14, and ROBO1 showed statistically significantly higher staining relative to the normal tumor tissue (p<0.001). We identified and validated plasma membrane molecules overexpressed in HCC compared to non-tumor tissue. Because GPC3, a well-known HCC-specific marker that is expressed in 75% of HCC, was identified using our approach, we are confident that that additional molecules may also represent promising HCC-selective targets. This work could facilitate the design, engineering, and testing of novel precision oncology imaging and therapeutic agents for HCC.

Convection-enhanced drug delivery for gliomas.

In spite of aggressive multi-modality treatments, patients diagnosed with anaplastic astrocytoma and glioblastoma continue to display poor median survival. The success of our current conventional and targeted chemotherapies are largely hindered by systemic- and neurotoxicity, as well as poor central nervous system (CNS) penetration. Interstitial drug administration via convection-enhanced delivery (CED) is an alternative that potentially overcomes systemic toxicities and CNS delivery issues by directly bypassing the blood–brain barrier (BBB). This novel approach not only allows for directed administration, but also allows for newer, tumor-selective agents, which would normally be excluded from the CNS due to molecular size alone. To date, randomized trials of CED therapy have yet to definitely show survival advantage as compared with today's standard of care, however, early studies appear to have been limited by “first generation” delivery techniques. Taking into consideration lessons learned from early trials along with decades of research, newer CED technologies and therapeutic agents are emerging, which are reviewed herein.

Structure-activity relationship of tumor-selective 5-substituted 2-amino-3-carboxymethylthiophene derivatives.

Methyl-2-amino-5-[2-(4-methoxyphenethyl)]thiophene-3-carboxylate (8 c) is the prototype of a well-defined class of tumor-selective agents. Compound 8 c preferentially inhibited the proliferation of a number of tumor cell lines including many human T-lymphoma/leukemia cells, but also several prostate, renal, central nervous system and liver tumor cell types. Instead, a broad variety of other tumor cell lines including B-lymphomas and HeLa cells were not affected. The tumor selectivity (TS; selectivity index or preferential suppression of CEM lymphoma (IC50 =0.90 μM) versus HeLa tumor cell carcinoma (IC50 =39 μM)) amounted up to ~43 for 8 c. At higher concentrations, the compound proved cytotoxic rather than cytostatic. The antiproliferative potency and selectivity of 8 c could be preserved by replacing the ethyl linker between the 2-amino-3-carboxymethylthiophene and the substituted aryl by a thioalkyl but not by an oxyalkyl nor an aminoalkyl. Among >50 novel 8 c derivatives, the 5-(4-ethyl- and 4-isopropylarylmethylthio)thiophene analogues, methyl-2-amino-5-((4-ethylphenylthio)methyl)thiophene-3-carboxylate (13 m) and methyl-2-amino-5-((4-isopropylphenylthio)methyl)thiophene-3-carboxylate (13 n), were more potent (IC50 : 0.3-0.4 μM) and selective (TS: 100-144) anti-T-lymphoma/leukemia agents than the prototype compound.

Abstract 579: 3, 3′-diindolylmethane enhances the effectiveness of Herceptin by upregulation of miR-200 through down-regulation of FoxM1 in breast cancer cells

Abstract Many patients with high levels of HER2/neu experience disease progression even when treated with Herceptin as a single agent. Current Herceptin-based combination therapies involving conventional chemotherapeutic drugs have been shown to increase survival rate in only a portion of patients with high levels of HER2/neu. Furthermore, these treatments are associated with several toxicities. Thus, there is a strong need for developing new tumor selective agents that can be co-administered with Herceptin successfully, and with minimal toxicity, to treat breast cancer patients whose tumors express high levels of HER2/neu. 3,3′-diindolylmethane (DIM), a cruciferous plant-derived and non-toxic chemopreventive agent, has been reported to selectively kill breast cancer cells without affecting normal cells and sensitizes breast cancer cells to chemotherapeutic agents. In this study, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER2/neu overexpressing) and MDA-MB-468 (HER2/neu-negative) breast cancer cell lines. We found that DIM could sensitize breast cancer cells to Herceptin by significantly reducing cell viability, which was associated with the induction of apoptosis and significant inhibition of colony formation when compared with single agent treatment. These results were also consistent with the down-regulation of Akt and NF-κB. Mechanistic investigations revealed a significant upregulation of miR-200, which resulted in the reduction of FoxM1 expression in DIM plus Herceptin-treated breast cancer cells. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients whose tumors express high levels of HER2/neu. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 579. doi:1538-7445.AM2012-579

Developing treatment strategies for rare cancers

Trial therapies for rare cancers are usually selected empirically and often fail during clinical testing. The poor efficiency and limited success of this process is hampered by a lack of accurate models with which to perform pre-clinical studies, and small patient numbers that are likely to include distinct subtypes. These challenges are further compounded by increasing evidence that many cancers are heterogeneous diseases, composed of numerous different subtypes that are likely to require different therapies [1, 2]. Using a recently developed accurate model of a specific subtype of ependymoma, we have developed an approach to advance the efficiency and speed with which treatments for rarer cancers may be discovered, developed and prioritized [3]. Ependymomas are rare tumors of the brain and spinal cord that are incurable in up to 40% of cases. Like many human cancers, previous studies have indicated that ependymoma is a composed of different subtypes [1, 2]. To develop rational treatments of ependymoma, we are generating mouse models of each subtype in order to model human cancer heterogeneity during preclinical drug development [1]. Our first model faithfully recapitulates the histology and transcriptome of one form of human cerebral ependymoma (subtype-D): making it an attractive tool for developing treatments for this specific group of patients as well as understanding the signaling pathways important in sustaining the disease [1]. Further, since our models are generated from specific types of neural stem cells (NSCs), we are also able to test if candidate therapies are toxic to closely related normal cell types. Pre-clinical tools that allow measurement of drug efficacy as well as toxicity against stem and progenitor cells are especially important for developing treatments of children with cancer whose organ systems are immature [1]. Our report in the September 2011 issue of Cancer Cell describes an integrated, multiplatform in vitro and in vivo high throughput screen (HTS) of drug efficacy against our mouse model of subtype-D ependymoma, and concurrent assessment of toxicity against the parental normal embryonic cerebral NSC. This comprehensive approach identified several new candidate therapies for clinical development including tumor selective agents, as well as novel insights into the biology of ependymoma [3]. Through a combination of growth inhibition and kinome-wide binding assays, our studies demonstrated that inhibitors of the Insulin Growth Factor receptor signal pathway and centrosome cycle e.g., inhibitors of PLK1, are highly potent against subtype-D ependymoma. These kinases have not been previously implicated in the biology of ependymoma. In addition to identifying kinases important for maintaining ependymoma, our study emphasizes the value of HTS for rationally repurposing existing anti-cancer drugs. Our HTS identified 5-Fluorouracil (5-FU) and two closely related compounds as highly selective and potent inhibitors of subtype-D ependymoma. Moreover, this potency and selectivity was confirmed in vivo. 5-FU has never been tested formally in patients with ependymoma. Indeed it is most unlikely that an early generation chemotherapeutic like 5-FU would ever be selected empirically for clinical trial. Consequently, we are now developing a clinical trial of 5-FU among children with ependymoma. We are currently using the same methodology employed to produce subtype-D tumors to generate mouse models of the remaining eight ependymoma subtypes. Together with our integrated in vitro and in vivo screening approach, this battery of models should allow us to complete in months, numerous single and multidrug preclinical trials that would take decades to conduct in the clinic. Preclinical strategies such as these hold significant promise to identify and prioritize therapies for rational clinical trials among patients with specific subtypes of cancer.

Oligo-branched peptides for tumor targeting: from magic bullets to magic forks

Background: Selective targeting of tumor cells is the final goal of research and drug discovery for cancer diagnosis, imaging and therapy. After the invention of hybridoma technology, the concept of magic bullet was introduced into the field of oncology, referring to selective killing of tumor cells, by specific antibodies. More recently, small molecules and peptides have also been proposed as selective targeting agents. Objective/methods: We analyze the state of the art of tumor-selective agents that are presently available and tested in clinical settings. A novel approach based on ‘armed’ oligo-branched peptides as tumor targeting agents, is discussed and compared with existing tumor-selective therapies mediated by antibodies, small molecules or monomeric peptides. Results/conclusions: Oligo-branched peptides could be novel drugs that combine the advantages of antibodies and small molecules.

Integrating the biological characteristics of oncolytic viruses and immune cells can optimize therapeutic benefits of cell-based delivery

Despite significant advances in the development of tumor-selective agents, strategies for effective delivery of these agents across biological barriers to cells within the tumor microenvironment has been limiting. One tactical approach to overcoming biological barriers is to use cells as delivery vehicles, and a variety of different cell types have been investigated with a range of agents. In addition to transporting agents with targeted delivery, cells can also produce their own tumoricidal effect, conceal a payload from an immune response, amplify a selective agent at the target site and facilitate an antitumor immune response. We have reported a therapeutic combination consisting of cytokine induced killer cells and an oncolytic vaccinia virus with many of these features that led to therapeutic synergy in animal models of human cancer. The synergy was due to the interaction of the two agents to enhance the antitumor benefits of each individual component. As both of these agents display broad tumor-targeting potential and possess unique tumor killing mechanisms, together they were able to recognize and destroy a far greater number of malignant cells within the heterogeneous tumor than either agent alone. Effective cancer therapy will require recognition and elimination of the root of the disease, the cancer stem cell, and the combination of CIK cells and oncolytic vaccinia viruses has this potential. To create effective tumor-selective agents the viruses are modified to take advantage of the unique biology of the cancer cell. Similarly, if we are to develop targeted therapies that are sufficiently multifaceted to eliminate cancer cells at all stages of disease, we should integrate the virus into the unique biology of the cell delivery vehicle.

Carboranyl thymidine analogues for neutron capture therapy

Neutron capture therapy (NCT) is a binary radio-chemotherapeutic modality for the treatment of cancer. A major focus of NCT-related research is the development of novel tumor-selective agents that serve as the chemical component in NCT. Thymidine analogues substituted with a boron-containing carborane cluster at the N3 position, designated 3CTAs (3-carboranyl thymidine analogues), constitute one class of these new improved NCT agents. Their chemical, structural and biological properties are discussed in this Feature Article.

P-965 Activity and mechanism of action of motexafin gadolinium inlung cancer: A tumor selective agent that induces redox stress

P-965 Activity and mechanism of action of motexafin gadolinium inlung cancer: A tumor selective agent that induces redox stress

Motexafin gadolinium: a redox-active tumor selective agent for the treatment of cancer

Redox regulation has been shown to be an important component of malignant cell survival and is a system that may be pharmacologically manipulated for the treatment of cancer. Motexafin gadolinium is a member of a class of rationally designed porphyrin-like molecules called texaphyrins. The rationale for its use in cancer therapy is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells and it has a novel mechanism of action as it induces redox stress, triggering apoptosis in a broad range of cancers. In vitro studies have shown that motexafin gadolinium is synergistic with radiation and varied chemotherapeutic agents. A phase III international study has shown that the onset of neurologic progression is significantly delayed in patients with brain metastases from lung cancer treated with whole-brain radiation and motexafin gadolinium (compared with radiation alone). Recent preclinical data have shown that motexafin gadolinium alone is cytotoxic to cancers such as multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia through redox and apoptotic pathways. Multiple clinical trials examining motexafin gadolinium as a single agent and in combination with radiation and/or chemotherapy for the treatment of solid and hematopoietic tumors are underway. Motexafin gadolinium is a novel tumor-targeted agent that disrupts redox balance in cancer cells by futile redox cycling. Motexafin gadolinium is currently in numerous hematology/oncology clinical trials for use as a single agent and in combination with chemotherapy and/or radiation therapy.

Capecitabine: Efficacy in advanced breast cancer

827 Background: Capecitabine is a 5 flouropyrimidine derivative that is an orally administered, tumor activated and tumor selective agent. The drug has shown an excellent response in anthracycline and taxane refractory metastatic breast cancer patients (pts). Methods: Pts of advanced breast cancer were treated with capecitabine alone or in combination with other agents.The response rate, toxicity, and time to tumor progression (TTP) was evaluated. Results: : 23 pts (between jan'2000 to march'03) with metastatic breast cancer were treated with capecitabine. The mean age was 55 years. All except one patients had received prior chemotherapy either as adjuvant and or for metastatic disease. Mean number of prior chemotherapy regimens received were two. 5-flurouracil was part of prior chemotherapy in ten patients. Mean number of metastatic sites were two. Only six patients had single site of metastasis. Site of metsastasis was lungs in 12, liver in 10, bones in 12, skin in 5. Sixteen patients received capecitab...

Capecitabine: Efficacy in advanced breast cancer

827 Background: Capecitabine is a 5 flouropyrimidine derivative that is an orally administered, tumor activated and tumor selective agent. The drug has shown an excellent response in anthracycline ...

Mitochondrial contributions to cancer cell physiology: redox balance, cell cycle, and drug resistance.

Alterations in the biochemistry of mitochondria have been associated with cell transformation and the acquisition of drug resistance to certain chemotherapeutic agents, suggesting that mitochondria may play a supportive role for the cancer cell phenotype. Mitochondria are multifunctional organelles that contribute to the cellular adenosine triphosphate (ATP) pool and cellular redox balance through the production of reactive oxygen intermediates (ROI). Our laboratory has focused on these mitochondrial functions in the context of cancer cell physiology to evaluate the potential role of mitochondria as controllers of tumour cell proliferation. Low concentrations of ROI have been implicated as messengers in intracellular signal transduction mechanisms; thus an imbalance of ROI production from the mitochondria may support cancer cell growth. In addition, suppression of mitochondrial ATP production can halt cell cycle progression at two energetic checkpoints, suggesting that the use of tumor-selective agents to reduce ATP production may offer a therapeutic target for cancer growth control.

The Search for New Antitumor Drugs from Blue-Green Algae

Abstract: Six to ten percent of the extracts of laboratory-cultured blue-green algae are significantly cytotoxic against human tumor cell lines. Structurally-unique cytotoxins have been isolated from most of the active extracts. Of the extracts of &gt;2000 cyanophytes examined to date, approximately 0.8% showed solid tumor selective cytotoxicity in the Corbett assay. The lipophilic extract of Nostoc sp. GSV 224 was by far the most cytotoxic and one of the few extracts that were both solid tumor and tumor selective. Cyclic depsipeptides called cryptophycins were found to be the solid tumor and tumor selective agents. In vivo studies on naturally-occurring cryptophycin-1 and semi-synthetic cryptophycin-8 indicate that these compounds are very active against a broad spectrrum of tumors implanted in mice, including multidrug-resistant tumors, and that a cryptophycin analog may eventually be evaluated in the clinic. Several cytotoxins from terrestrial cyanophytes have•structures that resemble those of some antineoplastic agents from marine invertebrates, suggesting that a more extensive cultivation and screening effort on marine cyanophytes could lead to more discoveries of new antitumor drugs.