Recent Patents on Anti-Cancer Drug Discovery - Volume 5, Issue 1, 2010

p53 Tumor suppressor gene encodes for a critical cellular protein that regulate the integrity of the cell and can induce cell cycle arrest and/or apoptosis upon cellular stresses of several origins, including chemotherapeutics. Loss of p53 function occurs in an estimated 50% of all cancers by mutations and deletions while in the presence of wild-type p53 alleles other mechanisms may affect the expression and activity of p53. Alternative mechanisms include methylation of the promoter of p53, deletion or epigenetic inactivation of the p53-positive regulator p14/ARF, elevated expression of the p53 regulators murine double minute 2 (MDM2) and MDMX, or alteration of upstream regulators of p53 such as the kinase ATM. MDM2 is a p53 E3 ubiquitin ligase that mediates the ubiquitin-dependent degradation of p53 while p14/ARF is a small MDM2-binding protein that controls the activity of MDM2 by displacing p53 and preventing its degradation. MDMX antagonize p53-dependent transcriptional control by interfering with p53 transactivation function. The understanding of the key role of p53 inactivation in cancer development generated considerable interest in developing compounds that are capable of restoring the p53 functions. Several patents have been issued on such compounds. Adenovirus-based p53 gene therapy as well as small molecules such as PRIMA that can restore the transcriptional transactivation function to mutant p53, or NUTLIN and RITA that interfere with MDM2-directed p53 degradation, have tested in a preclinical setting and some of these approaches are currently in clinical development.

Over the last decade, improvements in cancer therapies have prolonged the lives of cancer patients. Despite dramatic advances in imaging technology, surgical techniques, and adjuvant radio - and chemotherapy, the overall prognosis of this disease remains dismal. In light of this, there is an urgent need for the development of more effective therapies that can target residual disseminated tumor burden. Given the heterogeneity of tumors in general, no one strategy is likely to provide a satisfactory treatment regimen. Until the middle of the 20th century, medical treatments were limited to options like drugs, surgery, antibiotics, and radiation, but in the last years stem cells, due to their pathotropism, have become particularly attractive candidates not only to replace damaged tissue in degenerative pathologies, but also to deliver therapeutic molecules in patients with disseminated metastatic cancer. Worldwide there have been over 2000 patent applications involving human and non-human stem cells, of which one quarter refer to embryonic stem cells. Over one third of all stem cell applications and one quarter of all embryonic stem cell applications have been granted. The aim of this review is primarily to focus on the recent development of stem cell patents in cancer treatments.

In a recent patent, Wanebo HJ proposed to increase “apoptosis in a cancer cell comprising contacting the cancer cell with (a) oxaliplatin and (b) C6-ceramide, sequentially or concomitantly”. Cisplatin and derivatives are commonly used in the treatment of solid tumors. Cisplatin induces DNA adducts, which are responsible for the induction of a cellular stress, leading to the elimination of the proliferating cells by apoptosis. Recently, a different mechanism has been reported to explain the tumoricidal action of platinum-based agents. Indeed, cells treated with cisplatin exhibit an increase in plasma membrane fluidity through the activation of acid sphingomyelinase, the subsequent generation of ceramide and the redistribution of the death receptor CD95 into the lipid rafts. This latter event promotes the initiation of the apoptotic signal and the elimination of the malignant cells. In this review, we discuss the potential role played by the death receptor in the potentiation effect of exogenously added ceramide upon the oxaliplatin-mediated cytotoxic effect.

Aberrant activation of the PI3K/Akt/mTOR pathway is found in many types of cancer and thus plays a major role in breast cancer cell proliferation and anti-cancer drug resistance. The mechanisms involved in the activation of this pathway include: constitutively activated receptor tyrosine kinases (IGF/IGFR, ErbB, FGF/FGFR systems) leading to constitutive activation of PI3K; loss of PTEN function; PI3K mutations; aberrant activation of Akt, eIF4E, 4E-BP1 and p70S6K. These alterations trigger a cascade of biological events, from cell growth and proliferation to survival and migration, which contribute to tumor progression. Therefore, the PI3K/Akt/mTOR pathway is considered an attractive target for the development of novel anti-cancer molecules, and several specific tyrosine kinase inhibitors and signal transduction inhibitors specifically targeting the kinases involved in this pathway have been developed. Many of these inhibitors currently under clinical evaluation represent a promising approach for the treatment of breast cancer patients. This review provides an overview of the most recent patents, of pre-clinical and clinical studies of inhibitors targeting the different members and/or activators of the PI3K/Akt/mTOR pathway, used alone or in combination with other targeted agents for the treatment of breast cancer.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by unregulated growth of myeloid leukemia cells in the bone marrow and accumulation of these cells in the blood. CML represents approximately 15-20% of all adult leukemia and the disease development is clearly linked to the constitutively active tyrosine kinase of the chimeric protein BCR-ABL. It is encoded by the Bcr-Abl fusion gene sequence as the result of chromosome 9/22 translocation (Philadelphia chromosome) or other aberrant cytogenetic events. The development of targeted agents that specifically inhibit the tyrosine kinase (TK) activity of BCR-ABL has revolutionized the treatment of CML. Imatinib is now the first-line treatment for chronic phase CML, and several newer tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib have been added to the pharmacologic compendium. Despite the proven efficacy of TKIs to induce hematological and cytogenetic remission, a large majority of patients still has molecularly detectable disease. Therefore, new options are needed to improve therapeutic success in the treatment of leukemia. Pyrrolo[1,2-b][1,2,5] benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from CML patients at onset or from patients in blast crisis and who were imatinib- dasatinib- and nilotinib resistant. These results suggest that these compounds are promising agents for the treatment of leukemia. Due to the fact that the phenomenon of resistance to TKIs remains a major issue in the treatment of patients with CML, the identification of new drugs may be of clinical relevance. This review summarizes patents and papers dealing with the present understanding of mechanism of action and the most relevant data concerning TKs inhibition.

Radiofrequency (RF) ablation has gained great popularity in the treatment of Hepatocellular Carcinoma (HCC) on cirrhosis and is replacing Percutaneous Ethanol Injection (PEI) in treating 3cm or less HCC nodules. Its necrotic effect is more predictable than that of PEI and therefore RF can achieve a longer local tumor progression control and survival. In the last four years many data on its efficacy have been added in the Literature and long-term results on 3-5-year survival are available. In this review article data of the last 4 years on percutaneous RF ablation of HCC on cirrhosis are discussed in order to give an answer to questions put forward on this matter at 2000 EASL Barcelona Consensus Conference. Moreover, new perspectives in the percutaneous treatment of some form of advanced HCC (the so-called percutaneous thrombectomy) are presented together with some patents in the treatment of HCC.

Renal cell carcinoma (RCC) is one of the most common cancers in the United States. Recent achievements in translational research have lead to significant developments in treatment strategies for this malignancy. RCC is a richly vascular neoplasm. A better understanding of its biology has helped in the development of antiangiogenic therapy. Vascular endothelial growth factor (VEGF) is the most important molecular target in the treatment of RCC. Patents have been filed for anti-VEGF and other molecular pathways involved in the pathogenesis of RCC.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic area/target and therapeutic agents related to anti-cancer drug discovery.