Why did p53 gene therapy fail in ovarian cancer?

Promising preclinical and clinical data led to the initiation of an international randomised phase II/III trial of p53 gene-therapy trial for first-line treatment of patients with ovarian cancer. In that trial, replication-deficient adenoviral vectors carrying wild-type p53 were given intraperitoneally in combination with standard chemotherapy to patients with ovarian cancers harbouring p53 mutations. The study was closed after the first interim analysis because an adequate therapeutic benefit was not shown. In this review, we discuss the possible reasons for failure of p53 gene therapy, which include the multiple genetic changes in cancer and epigenetic dysregulations leading to aberrant silencing of genes. These complex interactions lead us to conclude that repair of single genes might not be a suitable strategy for the treatment of cancer. Moreover, dominant negative cross talk between ectopic wild-type p53 and recently identified dominant p53 mutants and splice variants of p63 and p73--which are frequently overexpressed in ovarian cancers--could seriously compromise the effectiveness of p53 gene therapy. Other substantial problems in targeting tumour cells with adenoviral vectors are the heterogeneity or lack of expression of coxsackie-adenovirus receptors and integrin co-receptors in ovarian tumours and the presence of adenovirus-neutralising antibodies in ovarian cancer-related ascites.     

Is angiogenesis inhibition the Holy Grail of cancer therapy?

Over the last several decades, oncology research and cancer treatment have concentrated primarily on the cancer cells. Unfortunately, despite the intensive quest to find new and more effective compounds for chemotherapy, the survival rate of patients has not significantly changed. In 1971 Judah Folkman proposed that a solid tumor cannot grow without inducing angiogenesis. Intensive search for molecules blocking the formation of a tumor-nourishing capillary network has identified several promising agents in experimental models. Some of these angiogenesis inhibitors are in clinical trials, but a clear statement about the efficacy cannot be made yet. What are the current trends in angiogenesis research? What areas should we intensively investigate? Can we find the Holy Grail of cancer therapy in the years to come in order to stop the ineffable suffering of millions of cancer patients?     

Is there place for radiotherapy in the treatment of advanced ovarian cancer?

BACKGROUND AND PURPOSE: Irradiation of advanced ovarian cancer has been performed during the years 1976-1984 with six-field technique. Results of this treatment in a long follow-up have never before been evaluated. MATERIAL AND METHODS: Seventy-five patients with stage IIb-IV of invasive ovarian cancer have been treated with a combination of surgery, radiotherapy and chemotherapy. The results of the treatment were compared with 98 patients treated during the year 1991-1992 with surgery and chemotherapy only. RESULTS: After controlling for the differences in background factors between the groups considered, there was still a significantly better survival rate for the patients treated with radiotherapy. CONCLUSION: The results suggest that the role of radiotherapy in advanced ovarian cancer should be investigated in a prospective randomized trial.     

Is there a role for intraperitoneal chemotherapy in the management of ovarian cancer?

Phase I and II clinical trial data have demonstrated the safety, pharmacokinetic advantage, and potential for enhanced cytotoxicity associated with the intraperitoneal administration of antineoplastic agents in the management of ovarian cancer. In two randomized phase III studies comparing the intraperitoneal and intravenous administration of cisplatin (Platinol) as initial therapy for small-volume residual advanced ovarian cancer, intraperitoneal delivery of the agent produced superior progression-free and overall survival. Reluctance to employ intraperitoneal cisplatin in the standard management of ovarian cancer appears to be related to the added time, effort, and potential morbidity associated with the approach, as well as a general preference for the less toxic, less complicated carboplatin (Paraplatin)-based regimen. However, existing data support the use of this unique method of drug delivery in carefully selected patients outside of the clinical trial setting.     

Gene therapy for breast cancer. — review of clinical gene therapy trials for breast cancer and mdr1 gene therapy trial in cancer institute hospital

Gene therapy for advanced breast cancer is anticipated to be a useful therapeutic approach. Strategies in ongoing clinical protocols can be divided into four groups: (1) suppression of oncogenes or transfer of tumor-suppressor genes; (2) enhancement of immunological response; (3) transfer of suicide genes; (4) protection of bone marrow using drug resistance genes. We have started a clinical study of multidrug resistance (MDR1) gene therapy. Advanced breast cancer patients received high dose chemotherapy and autologous peripheral blood stem cell transplantation(PBSCT)with MDR1-transduced hematopoietic cells, and then were treated with docetaxel. Two patients have been treated so far, and in vivo enrichment of MDR1-transduced cells with docetaxel treatment has been seen. Both patients are in complete remission and had no apparent adverse effects from the MDR1 gene transfer.     

Microbubble-enhanced ultrasound-mediated gene transfer – Towards the development of targeted gene therapy for cancer

Ultrasound-mediated gene transfer is emerging as a possible alternative to viral gene transfer, and pre-clinical data suggest that it may play a significant role in gene therapy-based approaches to the treatment of disease. As an extracorporeal stimulus, ultrasound can non-invasively and transiently compromise cell membrane permeability (sonoporation), thereby offering the promise of delivering either genes or oligonucleotide-based therapeutics to cells and tissues in a site-specific manner. The membrane-permeabilising effects of ultrasound can be greatly enhanced using microbubble preparations, many of which have, in the past, found application as ultrasound contrast agents. Because these ultrasound-responsive agents are highly amenable to surface modification it has been suggested that they may be exploited as ultrasound-responsive nucleic acid delivery vehicles. In this article we seek to explore the potential role ultrasound, in combination with microbubble-based agents, may play in providing site-specific gene therapy-based approaches for the treatment of cancer.     

The potential and feasibility of conservative therapy for the early stages of ovarian cancerĭ

Improvement in techniques of early diagnosis of ovarian cancer (OC) has highlighted the importance of development of methods of conservative surgery. Numerous researchers have failed so far to reach consensus on working out strategies of treatment. A retrospective analysis of clinico-morphological data on 176 patients with bordar-line and OC stage I (conservative surgery--46; radical--130) (1980-1985) showed that efficacy depended on tumor pattern rather than method of treatment. Given high risk of recurrence in unremoved ovary (2 out of 28 reproductive females), bilateral salpingo-oophorectomy without removal of the uterus is discussed as an alternative procedure of conservative therapy. Modern procedures of this therapy requiring accurate staging and monitoring can be carried out at large medical centers only.     

What is the role of neoadjuvant chemotherapy in the management of ovarian cancer?

Aggressive cytoreductive surgery followed by aggressive chemotherapy is the standard of care for advanced-stage ovarian cancer patients, among whom the greatest survival benefit is seen in those with no gross disease left after the initial surgical cytoreduction. Since this represents only 23% of stage III patients and 8% of stage IV patients, alternative strategies for patients who do not appear to be surgically cytoreducible to no macroscopic residual disease need to be identified. Neoadjuvant chemotherapy, which may offer a variety of benefits in this population, is one such strategy that is being evaluated in prospective randomized trials. This article reviews the current status of neoadjuvant chemotherapy for the management of women with advanced-stage ovarian cancer.     

Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?

Significant research has been conducted to better understand the extensive, heterogeneous molecular features of triple-negative breast cancer (TNBC). We reviewed published TNBC molecular classifications to identify major groupings that have potential for clinical trial development. With the ultimate aim to streamline translational medicine, we linked these categories of TNBC according to their gene-expression signatures, biological function, and clinical outcome. To this end, we define five potential clinically actionable groupings of TNBC: 1) basal-like TNBC with DNA-repair deficiency or growth factor pathways; 2) mesenchymal-like TNBC with epithelial-to-mesenchymal transition and cancer stem cell features; 3) immune-associated TNBC; 4) luminal/apocrine TNBC with androgen-receptor overexpression; and 5) HER2-enriched TNBC. For each defined subtype, we highlight the major biological pathways and discuss potential targeted therapies in TNBC that might abrogate disease progression. However, many of these potential targets need clinical validation by clinical trials. We have yet to know how we can enrich the targets by molecular classifications.