New Frontiers in the Medical Therapy of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. Summary: After controversial results of monotherapy, ICPIs have been mainly investigated in association with anti-angiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPIs-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first line treatment, the second line scenario relies mainly on tyrosine kinase inhibitors, which however, have not been formally trialed after ICPIs. Key messages: In this review we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

In silico and in vitro analysis of recombinant arginine deiminase from Pseudomonas furukawaii as a potential anticancer enzyme

Arginine deiminase (ADI) is a promising anticancer enzyme that can be employed in amino acid deprivation therapy for the treatment of various arginine auxotrophic tumors. In our previous work, Pseudomonas furukawaii was identified as a potent producer of ADI with optimum activity at physiological pH and temperature. The 3D structure of PfADI was modeled. Immunoinformatics analysis was also carried out to compare the immunogenicity of PfADI with MhADI (Mycoplasma hominis ADI, which is in phase III clinical trials). The PfADI was found to be less immunogenic in terms of number of linear and conformational B cell epitopes and T cell epitope density. The overall antigenicity and allergenicity of PfADI was also lower as compared to MhADI. Thus, the ADI coding arcA gene was cloned and expressed in E. coli BL21. Recombinant ADI of P. furukawaii (PfADI) was purified using affinity chromatography and its molecular mass was estimated to be ~46KDa. PfADI was found to effectively inhibit the HepG2 cells with an IC50 value of 0.1950 IU/ml. PfADI was characterized and the enzyme was found to be stable at human physiological conditions (pH 7 and 37 ⁰C temperature). The Km and Vmax values were found to be 1.90 mM and 1.83 µmol ml-1min-1 respectively. Thus the present in vitro and in silico studies establish PfADI as a potential anticancer drug candidate with improved efficacy and low immunogenicity.

Targeting KRAS G12C with Covalent Inhibitors

KRAS is the most frequently mutated oncogene in cancer. Following numerous attempts to inhibit KRAS spanning multiple decades, recent efforts aimed at covalently targeting the mutant cysteine of KRAS G12C have yielded very encouraging results. Indeed, one such molecule, sotorasib, has already received accelerated US Food and Drug Administration approval with phase III clinical trials currently underway. A second molecule, adagrasib, has also progressed to phase III, and several others have entered early-phase clinical trials. The success of these efforts has inspired an array of novel approaches targeting KRAS, with some reporting extension to the two most common oncogenic KRAS mutations, G12V and G12D. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

In Vitro Activity of Gepotidacin Against Gram-negative and Gram-positive Anaerobes

Gepotidacin (formerly GSK2140944) is a first in class triazaacenaphthylene antibacterial currently in Phase III clinical trials. When tested against Gram-negative ( n =333) and Gram-positive ( n =225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates (MIC 90 ) at concentrations of 4 and 2 μg/ml, respectively. Given gepotidacin’s in vitro activity against the anaerobic isolates tested, further study is warranted to better understand gepotidacin’s utility in the treatment of infections caused by clinically relevant anaerobic organisms.

Vaccine-induced immune responses against SARS-CoV-2 infections

Vaccination against coronavirus disease 2019 (COVID-19) is one of the most effective tools to curb the pandemic. Multiple vaccine candidates based on different platforms are available for emergency use presently. However, in common all the vaccines target spike protein, which is a dominant immunogen of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). Adequate immunogenicity and efficacy are demonstrated by many of the vaccines in clinical phase III trials. The emergence of the new variant of concern is believed to be associated with less susceptibility to the post-infection or post-vaccination mounted immunity. It is a global concern currently threatening the progression of the vaccination drive. Nevertheless, the results of the presently available phase III clinical trials promote COVID-19 vaccination to prevent disease severity and COVID-19 related deaths. Cross-immunity towards the new variants of concern especially against the South African variant is yet to be explored and managed adequately.

Omicron: A heavily mutated SARS-CoV-2 variant exhibits stronger binding to ACE2 and potently escape approved COVID-19 therapeutic antibodies

The new SARS-CoV-2 variant of concern “Omicron” was recently (Nov. 24th. 2021) spotted in South Africa and already spread around the world due to its enhanced transmissibility. The variant became conspicuous as it harbors more than thirty mutations in the spike protein with 15 mutations in the RBD region alone, potentially dampening the potency of therapeutic antibodies and enhancing the ACE2 binding. More worrying, Omicron infections have been reported in individuals who have received vaccines jabs in South Africa and Hong Kong. Here, we investigated the binding strength of Omicron with ACE2 and seven monoclonal antibodies that are either approved by FDA for COVID-19 therapy or undergoing phase III clinical trials. Computational mutagenesis and binding free energies could confirm that Omicron Spike binds ACE2 stronger than prototype SARS-CoV-2. Notably, three substitutions, i.e., T478K, Q493K, and Q498R, significantly contribute to the binding energies and doubled electrostatic potential of the RBDOmic-ACE2 complex. Instead of E484K substitution that helped neutralization escape of Beta, Gamma, and Mu variants, Omicron harbors E484A substitution. Together, T478K, Q493K, Q498R, and E484A substitutions contribute to a significant drop in the electrostatic potential energies between RBDOmic-mAbs, particularly in Etesevimab, Bamlanivimab, and CT-p59. CDR diversification could help regain the neutralization strength of these antibodies; however, we could not conduct this analysis to this end. Conclusively, our findings suggest that Omicron binds ACE2 with greater affinity, enhancing its infectivity and transmissibility. Mutations in the Spike are prudently devised by the virus that enhances the receptor binding and weakens the mAbs binding to escape the immune response.

Retinoid Agonists in the Targeting of Heterotopic Ossification

Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as all trans-retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to up-regulate the transcription of target genes. The RARs can also interact with target gene response elements in the absence of retinoids and exert a transcriptional repression function. Studies from several labs, including ours, showed that chondrogenic cell differentiation and cartilage maturation require (i) the absence of retinoid signaling and (ii) the repression function by unliganded RARs. These and related insights led to the proposition that synthetic retinoid agonists could thus represent pharmacological agents to inhibit heterotopic ossification (HO), a process that recapitulates developmental skeletogenesis and involves chondrogenesis, cartilage maturation, and endochondral ossification. One form of HO is acquired and is caused by injury, and another severe and often fatal form of it is genetic and occurs in patients with fibrodysplasia ossificans progressiva (FOP). Mouse models of FOP bearing mutant ACVR1R206H, characteristic of most FOP patients, were used to test the ability of the retinoid agonists selective for RARα and RARγ against spontaneous and injury-induced HO. The RARγ agonists were found to be most effective, and one such compound, palovarotene, was selected for testing in FOP patients. The safety and effectiveness data from recent and ongoing phase II and phase III clinical trials support the notion that palovarotene may represent a disease-modifying treatment for patients with FOP. The post hoc analyses showed substantial efficacy but also revealed side effects and complications, including premature growth plate closure in some patients. Skeletally immature patients will need to be carefully weighed in any future regulatory indications of palovarotene as an important therapeutic option in FOP.