Bispecific immunotherapy MEDI5752 or volrustomig and cervical cancer.

MEDI5752 is a monovalent bispecific immunotherapy and is strategically unique as it combines both anti programmed cell death 1 and anti cytotoxic T-lymphocyte-associated protein 4 action. This is one of the first of this kind of molecule. The development of this molecule had been very interesting which is not usually described in regular clinical oncology journals thus losing an important piece of history of an upcoming subject. Only some phase I results in such development is published so far and no full report on this is available till now. This effort will try to record the facts and chain of events which actually occurred in inventing and bringing it in phase III trial.

Controversy of tissue-agnostic approvals in immunotherapy and targeted therapy.

In recent years, approval of some immunotherapy based on markers such as dMMR, tumour mutational burden and other few such markers is not received well as shown in post-approval data published. The context of such approvals and controversies is discussed briefly.

Balstilimab and other immunotherapy for recurrent and metastatic cervical cancer.

Recurrent and metastatic cervical cancer is generally treated by cisplatin, paclitaxel, and bevacizumab with limited benefit this constituting an unmet need. Immune checkpoint inhibitors, namely the inhibitors of programmed death 1 and programmed death ligand 1 have been proved to be efficacious in the treatment of patients with advanced cervical cancer. Recently, a PD-1 inhibitor, pembrolizumab was approved for such cancer. However, there is much scope of improvement of current outcome. Dual blockade of cytotoxic T lymphocyte-associated protein 4 and PD-1 is an attractive therapeutic approach. It is used in other cancers and is currently proposed for cancer cervix also. Search is on for single or combined regimen showing efficacy in multiple pathological conditions of cancer cervix irrespective presence of PD-L1 in malignant tissue. An effort to meet such unmet need has culminated in inventing new immune checkpoint inhibitors namely PD-1 inhibitor, AGEN2034 (Balstilimab) and CTLA-4 inhibitor, AGEN1884 (Zalifrelimab).They have shown meaningful and durable activity as single-agent therapy in previously treated patients with persistent R/M CC in a large phase II trial (NCT03104699) in PD-L1 + and PD-L1- tumour. Responses were found both in squamous cell carcinoma & adenocarcinoma cell types. Balstilimab plus zalifrelimab combination (NCT03495882) produced improved clinical benefit over monotherapy as evidenced by higher relative response rates and longer response duration, as well as a manageable safety profile. Interesting development of this combination and other immunotherapies in R/M CC are discussed in this ensuing review.

Inhibitory role of a smart nano-trifattyglyceride of Moringa oleifera root in epithelial ovarian cancer, through attenuation of FSHR - c-Myc axis.

BACKGROUND AND AIM: Epithelial ovarian cancer has the deadliest prognosis amongst gynaecological cancers, warranting an unmet need for newer drug targets. Based on its anticancer as well as abortifacient potential, Moringa oleifera Lam. root was hypothesized to have some implications in follicle stimulating hormone receptor (FSHR) dependent cancers like epithelial ovarian cancer. EXPERIMENTAL PROCEDURE: Effect of Moringa oleifera Lam. root extract (MRE) was studied in epithelial ovarian cancer cell line through in vitro studies viz. MTT assay, clonogenic assay, cell cycle analysis, flow cytometry, western blot analysis, immunocytochemical analysis of FSHRand c-Myc expression and in vivo studies viz. effect of MRE in mice model of ovarian carcinoma. The structure of the active compound of MRE was elucidated following solvent extraction, purification through column chromatography, preparative TLC and bioactivity guided structural identification through 1H-NMR, 13C-NMR, DEPT-135, ESIMS,FT-IR spectrophotometry, UV-vis-NIR spectrophotometry and DFT study. RESULTS AND CONCLUSION: Crude MRE displayed cytotoxic activity, induced apoptosis, and attenuated expression of FSHR and c-Myc in ovarian cancer cell line OAW42. MRE also attenuated expression of CD31, FSHR, and c-Myc in tumour xenograft mouse model. Finally, the active compound purified from ethyl acetate-n-hexane subfraction ofMRE, that attenuated viability of ovarian carcinoma cell lines and reduced FSHR and c-Myc expression, was identified as a naturally hydrated-trifattyglyceride, showing aDFT-optimized folded amphipathic structure for easy transportation through hydrophilic and hydrophobic regions in a biological system, indicating its immense therapeutic relevance in epithelial ovarian carcinoma.

Immune checkpoints, their control by immunotherapy and ovarian cancer.

Immune checkpoints are new targets for manipulation of immunological control over malignant tumors. They provide an important means to manage especially recurrent and refractory cancers and those cancers where there is an unmet need such as recurrent melanoma, renal cell carcinoma and recurrent ovarian cancer. As a new development this subject is experiencing rapid progress and multiple avenues are opening up. However, there are many hurdles to overcome, requiring constant updating, especially for students of ovarian cancer, who are looking at it with much hope.

Immune Checkpoint Blockers and Ovarian Cancer.

Although the idea, called "cancer immunotherapy," is very appealing and has previously been shown to work in several mouse models of cancer, it has in general been very difficult to translate cancer immunotherapy approaches to humans. Because of this frustration, by the 1990s, many scientists and biotechnology companies had given up on the idea of cancer immunotherapy. After few years, first detection T-cell suppression of effect of cytotoxic T-lymphocyte antigen-4 (CTLA4) molecule was established. Antibody (Ab) to CTLA4 could increase T-cell starting a completely new age of tumor immunology. Immune checkpoints are new ways in manipulation of immunological control over malignant tumors. It has lent an important measure to manage, especially recurrent and refractory cancers and those cancer where there is an unmet need like recurrent melanoma, renal cell carcinoma, and recurrent ovarian cancer. As a new development, this subject is experiencing rapid progress, and multiple avenues are opening up. Although there are many hurdles to overcome this needs constant updating, especially for students of ovarian cancer who are looking at it with much hope.

PARP inhibitors and more.

Polyadenosine diphosphate (ADP) ribose polymerase (PARP) lends a panoramic view to the inner mystery of protection of integrity of deoxyribonucleic acid (DNA) in a cell genome. They are a balancing part of an even more dynamic equilibrium of normalcy against daily assaults. PARP finds its companion candidates in other tumor suppressors, with the most prominent and glaring one being breast cancer (BRCA) 1 and 2. The strength of both is split by PARP inhibitors, inculcating the synthetic lethality of tumor cell, which is now in the market for ovarian cancer treatment. There are many reasons for the resistance of such inhibitors, which are now becoming clinically important. These are seen along with other damage repair approaches.

Hyponatremia of non-small cell lung cancer: Indian experience.

BACKGROUND: Hyponatremia is a hazardous complication of lung cancer and its treatment. It is seen at presentation in approximately 15% of patients with small-cell lung cancer (SCLC) and 1% of patients with non-small cell lung cancer (NSCLC). Platinum compounds used as first-line agents along with taxols frequently cause hyponatremia. Till date there is no data on its prevalence in patients with advanced lung cancer in the Indian subcontinent. AIM: This study was undertaken to find out its incidence before and after institution of chemotherapy and to observe the results of treatment of hyponatremia in a group of lung cancer patient. MATERIALS AND METHODS: Forty patients with advanced lung cancer (25 patients with stage III disease and 15 with stage IV disease) were included in the study. Variables looked at included, but were not limited to, serum sodium, serum albumin, serum alkaline phosphatase, serum lactate dehydrogenase, and hemoglobin. These variables were measured as per the standard clinical laboratory procedure. No ethics approval was required as these parameters are routinely measured in such patients. RESULTS: In the chemo-naïve state, one out of five cases with SCLC (20%) had hyponatremia at presentation; among the 35 cases of NSCLC, 7 patients (20%) had hyponatremia at presentation, which is in sharp contrast to earlier reports of 1% prevalence of hyponatremia in this group. Among the 27 cases who died within 6 months, 11 had hyponatremia; this finding was statistically highly significant. CONCLUSION: In India, NSCLC patients are at high risk of having hyponatremia at presentation and this is significantly associated with a worse outcome.

Claudin and ovarian cancer.

Claudins are a family of proteins and the most important component of the tight junction. They constitute a paracellular barrier that controls the flow of molecules in the intercellular space of an epithelium. Although it seems that claudin should be down regulated in cancer cell, some claudins are, in fact highly elevated in various human cancers, including ovarian cancer. Whereas the functional significance of claudin overexpression in ovarian carcinoma is unclear, these proteins are important for migration, invasion, and survival of ovarian cancer cells. They clearly represent a general pathway in tumorigenesis, are a novel marker for ovarian cancer and may become a target for therapy or diagnosis of this disease.

Neurotrophin in obstetrics and gynaecology.

Since Rita Levi Montalcini and Stanley Cohen received Nobel Prize for their pioneering work on nerve growth factor (NGF), its role in female reproductive system has been reinforced in last two decades. The neurotrophins (NT) including nerve growth factor (NGF) are a family of related growth factors and their respective receptor tyrosine kinases that are of major importance in the regulation of neuronal survival and differentiation. While role of NGF in mast cell-mediated egg implantation and inhibition of rejection were primary concern at their time, in the ovary NGF can help in the differentiation process by which ovarian follicles become responsive to gonadotrophins. They help in follicular maturation, steroid secretion and ovulation in the ovary, by inducing the FSH receptor (FSHR). Due to the pleiotropism, NGF is mandatory for the success of pregnancy, while progesterone helping to maintain local levels of NGF in utero. In endometriosisi and polycystic ovarian disease it has major role to play. An autocrine role of NGF in breast cancer and epithelial ovarian cancer (EOC) is evident now. Thus its study will infuse new insight in diseases of both obstetrics and gynaecology.

Follicle stimulating hormone receptor in ovarian surface epithelium and epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) has remained an enigmatic disease, the etiology of which is mostly unknown. Considering the age incidence around menopause, a "gonadotrophin theory" has been proposed, and considering the association with infertility, an "incessant ovulation" theory has been proposed. EOC originates from ovarian surface epithelium (OSE), which not only secretes cytokines/growth factors and steroids but expresses gonadotrophin and steroid hormone receptors as well. The most important gonadotrophin receptor is the follicle stimulating hormone receptor (FSHR), which has definite oncogenic potential and is a probable candidate for oncogenesis. In this article, we review existing knowledge of FSHR in ovary, in OSE, and in epithelial ovarian cancer and try to establish relative importance of this receptor over its ligand. A systematic review through PubMed was done on the subject of FSHR and its metabolism. For the obvious difficulty of meager amounts of tissue available, most of studies so far see it in granulosa cells and cell lines rather than in OSE. Thus, effort was made to deduce workable knowledge that can establish its role and can then be applied in OSE and EOC. There is great deal of information regarding metabolism of FSHR, including regulation of its gene expression, isoforms, and pathways of desensitization and degradation with which ovarian cancer etiology researchers have to be familiar with, and there are a number of steps where manipulation may stop carcinogenesis. Hormone therapy of such cancer has so far been only mildly active, probably because we do not understand the role and mechanism of action of FSH and FSHR in the hypothalamo-pituitary-ovarian axis in development of such cancer.

Liposomal doxorubicin in suspected ovarian carcinoma patient with very low creatinine clearance test value.

A 74-year-old woman presented with moderate ascites with diagnostic features of adenocarcinoma of the ovary. She was given 1 course of cisplatin- and paclitaxel-based chemotherapy but did not have her creatinine clearance tested, which was consequently found to be very low. She subsequently presented with gross debilitating symptoms and toxicity. However, she tolerated 20 mg/m(2) dose of liposomal doxorubicin every 4 weeks and was a good responder. Only 1 previous study of use of doxorubicin was found in such a low level of creatinine clearance.

Follicle stimulating hormone receptor (FSHR) antagonist and epithelial ovarian cancer (EOC).

INTRODUCTION: Follicle stimulating hormone receptor (FSHR), a G-protein coupled receptor present in granulosa cell of ovary is a unique transmembrane molecule pivotal in ovulation process. Its agonist and antagonists has remained the subject of interest to the reproductive biologists. It seems worthwhile to see what is new research on FSHR and whether they will be of any help in epithelial ovarian cancer. METHODS: Pubmed and medline search was made from January 2006 to April 2006 to find out current development of FSHR antagonist research and role of FSHR in epithelial ovarian cancer RESULTS: Effort to develop FSHR antagonist was mainly aimed at peptide antibody development. Breakthrough discovery of nonapeptide FSHR antagonist molecules, like suramin, compound 1 and compound 10 are noted. This is discussed in the context of nonsteroidal contraceptive for male and female. FSHR was found to have a distinguished role in precipitation of epithelial ovarian cancer. Hence, these antagonists might have a novel role to play in their treatment. CONCLUSION: Author proposes the trial of these molecules as novel anticancer agents in epithelial ovarian cancer.