Recent Patents on Anti-Cancer Drug Discovery - Volume 14, Issue 3, 2019

Background: Malignant melanoma is a skin cancer responsible for 90% of cutaneous cancer- related deaths. In recent years, breakthroughs in treatment strategy have revolutionized the prognosis in both early and advanced melanoma patients. In particular, treatment with monoclonal antibodies targeting co-inhibitory checkpoints or specific molecular pathways leads to a new era of promising options, by prolonging the survival time of these patients. Moreover, unlike the chemotherapy that was used until some time ago, these new drugs have a good and more manageable toxicity profile. However, because of the recent introduction in clinical practice of the new agents, there is a learning curve among physicians regarding early recognition and management of the associated side effects. Objectives: The analysis of the toxicity profiles of the different agents currently studied for the treatment of early and advanced melanoma, and the description of several relevant recent patents in this field, are the aims of this review. Methods: This is a systematically conducted review based on current clinical guidelines and on international Pharmacovigilance databases (AERS-Eudravigilance - WHO Vigibase). Results: Our systematic analysis outlines a comprehensive overview of the pharmacology, clinical application and the safety of recent anticancer drugs to treat melanoma, which can be an essential instrument for health professionals and researchers. Conclusion: The new oncological therapies against melanoma are based on increasingly specific biological and immunological targets. For this reason, the potential toxicities that are expected from patients would be less relevant than the systemic "classical" chemotherapy. However, the new therapies are not free from the risk of causing adverse reactions, some of which must be managed promptly and appropriately; moreover, the multiplicity of the metabolic pathways exposes the new target therapies to relevant potential interactions. This review can help to understand how important it is not to underestimate potential adverse drug reactions related to new targeted therapies.

Background: Thyroid cancer is the most common endocrine neoplasia and represents approximately 1.5% to 2.1% of all cancers diagnosed annually worldwide. Iodine Refractory Differentiated Thyroid Carcinoma (RR-DTC) and advanced/metastatic medullary thyroid carcinoma are relatively uncommon yet prognostically significant thyroid cancers. Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers, including thyroid cancer. Many Multi-Kinase Inhibitors (MKIs) which are now FDA-/EMAapproved for thyroid cancer have shown clinical benefit in patients with advanced cancer. Treatmentrelated toxicities occur frequently with these drugs and can be severe or life-threatening. Objectives: This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field. Methods: We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions. Results: This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer. Conclusion: It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment.

Background: Lung cancer is the most frequent cause of cancer-related death. In the last decades, the introduction of targeted therapies and more recently, of immunotherapy, has led to significant improvements in different outcomes of this malignant neoplasm. Objective: The present review provides a balanced overview of most recent targeted therapies and immunotherapies patented for the treatment of lung cancer. Methods: An extensive scientific literature and patent databases search were performed to identify peerreviewed studies containing information on recently patented drugs for the treatment of lung cancer, with a particular focus on their safety data and recently patented combinations. Results: The development of therapies directed to different pathways involved in the tumor angiogenesis, proliferation, and metastasis has transformed the clinical practice of lung malignancies. Several clinical trials have shown an improvement in terms of progression-free survival and overall survival in patients with advanced/metastatic lung cancer. Safety data, extracted from clinical trials and from the WHO global database of adverse drug reactions (VigiAccessTM database), show that recently patented drugs for the treatment of lung cancer are well-tolerated and most of the adverse events reported are mild to moderate. Conclusion: Currently, a consistent number of new drugs and combinations have been introduced for the treatment of patients with advanced-stage lung cancer. Safety data remain essential to better assess the long-term risk/benefit ratio of these valuable emerging therapies. The new patents’ development could provide further significant improvements for lung cancer treatment.

Background: The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins. Objective: Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment. Methods: We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. Results: HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions. Conclusion: Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.

Background: A previous genome-wide association study showed that hTERT rs10069690 and rs2736100 polymorphisms were associated with thyroid cancer risk. Objective: This study further investigated the association between increased risk and clinicopathologic characteristics for Papillary Thyroid Carcinoma (PTC) and hTERT polymorphisms rs10069690 or rs2736100 in a Chinese female population. Methods: The hTERT genotypes of 276 PTC patients and 345 healthy subjects were determined with regard to SNPs rs10069690 and rs2736100. The association between these SNPs and the risk of PTC and clinicopathologic characteristics was investigated by logistic regression. Results: We found a significant difference between PTC and rs10069690 (Odds Ratio (OR) = 1.515; P = 0.005), but not between PTC and rs2736100. When the analysis was limited to females, rs10069690 and rs2736100 were both associated with increased risk for PTC in female individuals (OR = 1.647, P = 0.007; OR = 1.339, P = 0.041, respectively). Further haplotype analysis revealed a stimulative effect of haplotypes TC and CA of TERT rs10069690-rs2736100, which increased risk for PTC in female individuals (OR = 1.579, P = 0.014; OR = 0.726, P = 0.025, respectively). Furthermore, the heterozygote A/C of rs2736100 showed significant difference for age (OR = 0.514, P = 0.047). Conclusion: Our finding suggests that hTERT polymorphisms rs10069690 and rs2736100 are associated with increased risk for PTC in Chinese female population and rs2736100 may be related to age. Consistent with US20170360914 and US20170232075, they are expected to be a potential molecular target for anti-cancer therapy.

Background: Due to the low water solubility of Docetaxel (DTX), it is formulated with ethanol and Tween 80 with lots of side effects. For this reason, special attention has been paid to formulate it in new drug nano-carriers. Objective: The goal of this study was to evaluate the safety, antitumor activity and tissue distribution of the novel synthesized Raloxifene (RA) targeted polymeric micelles. Methods: DTX-loaded RA-targeted polymeric micelles composed of poly(styrene-maleic acid)- poly(amide-ether-ester-imide)-poly(ethylene glycol) (SMA-PAEE-PEG) were prepared and their antitumor activity was studied in MC4-L2 tumor-bearing mice compared with non-targeted micelles and free DTX. Safety of the micelles was studied by Hematoxylin and Eosin (H) staining of tumors and major organs of the mice. The drug accumulation in the tumor and major organs was measured by HPLC method. Results: The results showed better tumor growth inhibition and increased survival of mice treated with DTX-loaded in targeted micelles compared to the non-targeted micelles and free DTX. Histopathological studies, H staining of tumors and immunohistochemical examination showed the potential of DTX-loaded RA-targeted micelles to inhibit tumor cells proliferation. The higher accumulation of the DTX in the tumor tissue after injection of the micelles compared to the free DTX may indicate the higher uptake of the targeted micelles by the G-Protein-Coupled Estrogen Receptors (GPER). Conclusion: The results indicate that RA-conjugated polymeric micelles may be a strong and effective drug delivery system for DTX therapy and uptake of the drug into tumor cells, and overcome the disadvantages and side effects of conventional DTX.