Cancer Gene Therapy

The approval of cancer drugs by the United States Food and Drug Administration have increased progressively over the past
two decades with a trend towards the adoption of targeted drugs which are more precise in their mechanisms of action.
Advances in genetic profiling, immunohistochemical analysis of tumors, biomarker development, and a renewed appreciation
of the tumor microenvironment have produced a new generation of targeted chemical and biological therapies. These
innovations are the fruits of basic research in molecular and cellular biology, biochemistry, and immunology.
Purpose: To elucidate the paradigm shift in cancer drug development that has impacted the lives of patients in terms of
quality of life, tumor responses, over-all survival, and potential cures.
Methods: This review is based on an examination of published literature using the National Center for Biotechnology Information
(NCBI), the USFDA/National Institutes of Health (NIH) websites, USFDA approved product literature, Center Watch,
industry-sponsored websites, and clinicaltrials.gov websites. Cancer drugs are classified and described based on their proposed
mechanisms of action.
Results: The last two decades witnessed a paradigm shift in cancer drug development toward molecular targeted therapies
and targeted drug delivery. Molecular targets include tyrosine kinase receptors, serinethreonine kinase signaling pathways,
and growth factors. An increasing number of antibody-based therapies have emerged. Improvements in drug delivery include
the use of albumin-bound nanoparticles for targeting the enhanced permeability and retention effects seen in tumors.
Recent developments in the fields of cancer immunotherapy and gene therapy are exceedingly encouraging.
Conclusions: A review of USFDA-approved drugs and cancer drugs in clinical development, based on their mechanisms of
action, is presented. The progressive shift in cancer drug development towards targeted therapies and cancer immunotherapy
raises hope for improved outcomes for many types of cancer in the future.

Although mortality from colorectal cancer (CRC) is decreasing, CRC is still the second highest cause of cancer-related deaths in America. Chemotherapy and radiation therapy now have central roles in our strategies to fight cancer, although we continue to lack novel strategies overcoming therapeutic resistance. Molecular mechanisms of therapeutic resistance in CRC continue to be under intense investigation. In this review, we highlight the recent evidence linking epithelial-to-mesenchymal transition (EMT) with aggressive tumor biology as well as with the cancer stem cells (CSCs) across multiple organ systems including colon cancer. Furthermore, in the era of neo-adjuvant treatment, the clinical implications are concerning that our treatments may have the potential to induce more aggressive cancer cells through EMT, perhaps even generating CSCs more capable of metastasis and further resistant to treatment. This concern and potential reality highlights the critical need for further und...

We have previously shown that herpes simplex virus type 1 (HSV-1) infection is associated with early destabilization/degradation of infected cell mRNAs and consequent shutoff of host protein synthesis by the activity of the virion-associated host shutoff (vhs) UL41 protein. Wild-type (wt) virus destabilized/degraded the housekeeping β-actin and α-tubulin mRNAs as well host stress functions, like the heat shock 70 protein induced postinfection. vhs mutants did not degrade the mRNAs. Elaborate studies by others have been concerned with the mode of mRNA degradation and the mRNAs affected. We now describe vhs activity in primary cultures of mouse cerebellar granule neurons (CGNs). Specifically, (i) upon infection in the presence of actinomycin D to test activity of input viral particles, there was a generalized inhibition of protein synthesis, which depended on the input multiplicity of infection (MOI). (ii) Low-MOI infection with vhs-1 mutant virus was associated with increased synthes...

A herpes simplex thymidine kinase – green fluorescent protein (TK-GFP) fusion gene was constructed to couple a
marker gene to a therapeutic gene. For testing the utility of the fusion gene, it was cloned into four different viral
vectors: Semliki forest virus (SFV), Sindbis virus, adenovirus and lentivirus. The produced viral TK-GFP vectors
were then used to test their transduction efficiency on different tumor cells and especially the relationship between
TK gene transfer and treatment result with prodrug ganciclovir (GCV). When the efficiency of the other three viral
vectors were compared to adenoviral vector, a commonly used tool in cancer gene therapy, the alphaviral vectors
SFV and Sindbis performed better on glioma cells, but were less efficient on renal carcinoma cells. On the other
hand, an HIV-1 –based, VSV-G pseudotyped lentiviral vector was efficient on all cell lines tested, suggesting the
potential of this vector type for cancer gene therapy. GCV-sensitivity studies revealed that regardless of the vector
type used, the treatment result was directly proportional to the gene transfer efficiency (not to the multiplicity of
infection). However, good gene transfer rate alone is not always sufficient: twenty- percent efficiency was enough to
cause adequate cytotoxicity with 5 mg/ml GCV in both of the glioma cell lines, whereas even higher than 80%
transduction was not enough to successfully treat Caki-2 cells under the same conditions. When the bystander effect
was examined, Caki-2 cells were shown to display a much weaker effect than the glioma cells. Our results
demonstrate the benefit of TK-GFP fusion gene in cancer gene therapy research and emphasize the importance of
finding an appropriate vector type for each tumor, as well as testing the presence of bystander effect before
continuing with TK/GCV approach.

Noninvasive imaging in lung metastatic tumor models is used infrequently because of technical limitations in detecting metastases. We have previously used 2'-fluoro-2'-deoxy-5-iodo-1-beta-d-arabinofuranosyluracil labeled with (131)I ((131)I-FIAU) and demonstrated the applicability of noninvasive imaging for monitoring cancer gene therapy in an experimental animal model of herpes simplex virus type 1 thymidine kinase (HSV1-tk)-expressing tumor xenografts. We have now used the same animal model to effectively and noninvasively monitor the location, magnitude, and duration of therapeutic gene expression over time for the lung metastases model. To improve the detectability of lung metastases, an experimental blood-borne lung metastases model in mice was established using intravenously administered HSV1-tk-expressing NG4TL4 fibrosarcoma cells (NG4TL4-TK) and simulated the clinical application of HSV1-tk plus ganciclovir (GCV) prodrug activation gene therapy. The efficacy of nonin...

Enhanced tumor delivery of plasmid DNA with electric pulses in vivo has been confirmed in many preclinical models. Intratumor electrotransfer of plasmids encoding therapeutic molecules has reached Phase II clinical trials. In multiple preclinical studies, a reduction in tumor growth, increased survival or complete tumor regression have been observed in control groups in which vector or backbone plasmid DNA electrotransfer was performed. This study explores factors that could produce this antitumor effect. The specific electrotransfer pulse protocol employed significantly potentiated the regression. Tumor regression was observed after delivery of single-stranded or double-stranded DNA with or without CpG motifs in both immunocompetent and immunodeficient mice, indicating the involvement of the innate immune system in response to DNA. In conclusion, this study demonstrated that the observed antitumor effects are not due to a single factor, but to a combination of factors.Cancer Gene T...