Monoclonal antibody (mAb) and chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising clinical outcomes treating hematological malignancies. However, disease relapse remains problematic and likely caused by loss of therapeutic targets on tumors.1 Thus, novel immunotherapies against alternative targets are urgently needed. We developed a new therapeutic mAb against B-cell activating factor receptor (BAFF-R), a tumor necrosis factor primarily expressed on B cells and B-cell lymphoma and leukemia.2 The mAb induced antibody-dependent cellular cytotoxicity against a panel of human B-cell tumor lines and primary tumors including samples from relapse after rituximab treatment. Potent in vivo antitumor effects were observed on two drug-resistant human lymphoma models (rituximab- and ibrutinibresistant lymphomas) resulting in eradication of implanted tumors and long-term, tumor-free survival (P<0.001).3 Adapting the antibody binding domain, we developed a BAFF-R CAR containing CD3 and 4-1BB intracellular signaling domains. BAFF-R CAR-T cells had significant activation and killing against various malignant B-cell lines and primary tumors (NHLs, acute lymphoblastic leukemias, and chronic lymphocytic leukemias), in vitro. Tumor eradication and tumor-free survival was repeatedly observed in human lymphoma xenograft models including mantle cell (JeKo-1, Z-138) and Burkitt (Raji) lymphomas in NSG mice (P<0.01). Moreover, our BAFF-R CAR-T therapy eradicated CD19KO Z-138 tumors that is resistant to CD19-CAR treatment in NSG mice (*P<0.01 Figure). Altogether, our results strongly support the translational significance of our novel BAFF-R targeting immunotherapies, particularly for the major unmet clinical need of drug-resistant relapses in B-cell lymphoma and leukemia. 

Of 71 anti-cancer drugs for solid tumors approved by the FDA between 2002 and 2014, the median gains in progression-free and overall survival are ~2 months. These observations suggest two potential unmet clinical needs: (1) the existence of drug resistance and (2) the importance of patient stratification. In other words, it is imperative to implement a companion diagnostic biomarker along with drug discovery pipeline. To address these two questions, we have accessed several big data to identify old drugs for anti-cancer drug discovery. Firstly, resistance to chemotherapy or targeted therapy is a major problem for systemic lung cancer treatment. Such resistance may be explained by cancer stem-like cell (CSC) theory. By using the Connectivity Map dataset, we have identified phenothiazine-like antipsychotic drugs which may reverse the CSC-associated gene expression. Further, the in vitro and in vivo experiments have validated its anti-CSC effects. This study demonstrated a novel platform for screening potential anti-CSC drugs, which may overcome the drug resistance. Secondly, synthetic lethality (SL) has emerged as a novel anti-cancer strategy. SL is an interaction between two genes such that simultaneous perturbations of two genes result in cell death or a dramatic decrease of cell viability, whereas a perturbation of either gene alone is not lethal. We evaluated several old oncology drugs and mapped their corresponding SL pairs. The predicted results were further validated via in vitro biochemical assay and retrospectively sequencing of patient specimens. In conclusion, this systematic analysis strategy could rapidly place old drugs with biomarkers for clinical study.

Our group works on Glioblastoma Multiforme (GBM) tumours. In collaboration with neurosurgeons we obtain tumours from the tumorotheque, which are disassociated mechanically with the aim of recuperating all the cells present in the tumour. It is well known that the Glioblastoma consists of a heterogeneous cell population and our culture conditions allow for the proliferation and survival of all the cell types present in the original tumour. This first part would represent the deconstruction of the tumour and at present we have at our disposition a collection of 80 primary cultures of GBMs. Initial experiments have shown that in the present of “Cancer-associated Fibroblasts” or CAFs, tumour cells proliferate more and respond less to irradiation and temolozolamide (TMZ) (principal treatment for GBM). For the second part of our project namely the “reconstruction” we have developed a system of 3D-bioprinting, which would include adding a mixture of primary GBM cells and CAFs in a matrix of hydrogel and collagen that would represent our bioink. Using a 3D-bioprinter we would then reconstruct the tumour. The reconstructed tumour scaffolds should all be identical and contain similar cell numbers that are important in the analyses. Once tumour cell aggregates are visible in the scaffolds, these scaffolds would be used to determine the role of CAFs in the “protection – survival” of the tumour after chemo- (100 µM TMZ) and/or radiotherapy.

Cachexia is a devastating clinical condition frequently associated with many types of cancers and is also a common consequence of chemotherapy administration. Based on the Traditional Chinese Medicine (TCM) theory, the formula empirically used as invigorators for treating weakness, fatigue and poor appetite are often used for improving cachectic conditions. However, comprehensive evidence to characterize the anti-cachexia mechanism of TCM remains largely needed. In this study, we employed Lewis lung carcinoma (LLC)-induced cancer cachectic mice model to demonstrate the anti-cachectic effect of a novel combination of decoction referred to as Zhen-Qi Sijunzi (ZQ-SJZ). Administration of ZQ-SJZ can recover tumor- and/or cisplatin-induced body weight loss, intestinal mucosal damage, as well as forelimb grip strength and myofiber size. Mechanistically, ZQ-SJZ increased the levels of myogenic proteins, such as MyHC and myogenin, and decreased the atrophy-related protein, atrogin-1 in cisplatin-treated C2C12 myotubes in vitro. Moreover, cisplatin-induced mitochondria dysfunction can be hampered by the co-administration of ZQ-SJZ, by which it recovered cisplatin-mediated decrease of PGC-1a and PKM1. Given that PGC-1a plays a role in both mitochondria biogenesis and myogenesis, ZQ-SJZ likely plays a role in the modulation of mitochondrial function and subsequent myogenesis. Notably, ZQ-SJZ administration significantly prolonged the survival of LLC-induced cachectic mice under cisplatin treatment, indicating its profound activity in anti-cachexia and chemo-toxicity alleviation. Taken together, these results demonstrated the anti-cachectic mechanism of ZQ-SJZ and its potential use as a palliative strategy to improve the efficacy of chemotherapy.

Despite the known fact that immunoglobulins are expressed among cancer cells, their roles in cancer immunology are still not fully understood. In 1987, a monoclonal antibody, RP215 was generated and later shown to recognize mainly a carbohydrateassociated (O-glycan) epitope located in the variable regions of heavy chain immunoglobulins (designated in general as CA215) expressed on the surface of cancer cells, but not those from normal B cells. Biological and immunological studies of cancerous immunoglobulins have been performed extensively with RP215 as the unique probe. Both anti-immunoglobulins and RP215 were shown to induce apoptosis and complementdependent cytotoxicity reactions to culturing cancer cells. In vivo nude mouse animal models also revealed dose-dependent reductions of implanted tumor upon injections of RP215. Gene regulation studies were performed by using semi-quantitative PCR with genes involved in immunoglobulins expressions and toll-like receptors. The binding of RP215 and antiimmunoglobulins to cancer cells was shown to affect similar levels of gene expressions with excellent mutual correlations (R2 ≥ 0.90). Human serum proteins which interact with affinitypurified CA215 and/or cancerous immunoglobulins were identified and found to consist of those with known pro-cancer or anti-cancer properties. These observations led to the hypothesis of dual functional roles of cancerous immunoglobulins in cancer cells. Interactions with relevant human serum proteins may be essential for proliferation/growth of cancer cells and may also be required to neutralize those hostile to cancer cells. In addition, RP215-based enzyme immunoassay kits are beneficial in monitoring serum levels of CA215 or cancerous immunoglobulins among cancer patients. Anti-cancer and pancancer nature of CA215 revealed that RP215 can be an ideal candidate for the development of anti-cancer drugs or therapeutic treatments. RP215-linked chimeric antigen receptor (CAR)-T cell therapy technology has been attempted for anti-cancer treatments, through a series of CAR construction and validations by cytotoxic cell killing and cytokine activity release assays. In conclusion, dual distinct functional roles of widespread cancerous immunoglobulins among cancer cells have been demonstrated for the potential applications of RP215 in therapeutic treatments of many human cancers.

The K-BTE device simply releases bio electrons photons. Enriched by natural acids these bio electrons photons become capable of dissolving unhealthy particles in fiber tissue. Then dissolving and dispersing   unhealthy particles, it means number of sick particles, dead cells and oxidized proteins from fiber tissue without harm to the healthy cells. This dissolving and dispersing of extreme bad and dangerous unhealthy particles can operate in the brain or any other physical organ. In the brain, any kind of neurological disorders can be checked searching for deep painfully affected areas and then reversed by enriched bio electron photons. The same healing capability occurs identically in an atrophied muscle, bone and cartilage tissue. Also works for plaque in the entire vascular system by dispersing and healing.  The ever present keynote of the K-BTE device is always the lack of harm to healthy cells.

The K-BTE device attracts and transfers light of sun quanta particles consisting by its structure of element concentric rings which are consisted by bio-chemical charges of bio photons and electron neutrinos penetrating directly into the brain. This light injection fosters the regeneration, recovery and re-growth of neurons in the brain. This enlightening process facilitates the brain tissue to regain its ability to send impulses throughout the body while simultaneously improving mobility and homeostasis.

Despite the known fact that immunoglobulins are expressed among cancer cells, their roles in cancer immunology are still not fully understood. In 1987, a monoclonal antibody, RP215 was generated and later shown to recognize mainly a carbohydrateassociated (O-glycan) epitope located in the variable regions of heavy chain immunoglobulins (designated in general as CA215) expressed on the surface of cancer cells, but not those from normal B cells. Biological and immunological studies of cancerous immunoglobulins have been performed extensively with RP215 as the unique probe. Both anti-immunoglobulins and RP215 were shown to induce apoptosis and complementdependent cytotoxicity reactions to culturing cancer cells. In vivo nude mouse animal models also revealed dose-dependent reductions of implanted tumor upon injections of RP215. Gene regulation studies were performed by using semi-quantitative PCR with genes involved in immunoglobulins expressions and toll-like receptors. The binding of RP215 and antiimmunoglobulins to cancer cells was shown to affect similar levels of gene expressions with excellent mutual correlations (R2 ≥ 0.90). Human serum proteins which interact with affinitypurified CA215 and/or cancerous immunoglobulins were identified and found to consist of those with known pro-cancer or anti-cancer properties. These observations led to the hypothesis of dual functional roles of cancerous immunoglobulins in cancer cells. Interactions with relevant human serum proteins may be essential for proliferation/growth of cancer cells and may also be required to neutralize those hostile to cancer cells. In addition, RP215-based enzyme immunoassay kits are beneficial in monitoring serum levels of CA215 or cancerous immunoglobulins among cancer patients. Anti-cancer and pancancer nature of CA215 revealed that RP215 can be an ideal candidate for the development of anti-cancer drugs or therapeutic treatments. RP215-linked chimeric antigen receptor (CAR)-T cell therapy technology has been attempted for anti-cancer treatments, through a series of CAR construction and validations by cytotoxic cell killing and cytokine activity release assays. In conclusion, dual distinct functional roles of widespread cancerous immunoglobulins among cancer cells have been demonstrated for the potential applications of RP215 in therapeutic treatments of many human cancers.

Cardiotoxic effects related to anticancer drugs are among the leading causes of morbidity and mortality in cancer patients treated with Trastuzumab (T), Pertuzumab (P) and Trastuzumab-DM1 (TDM1) [1-3]. Sacubitril-valsartan (LCZ 696), a drug used for the treatment of heart failure in patients with a reduced ejection fraction, is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan.

In this study, we aim to assess whether LCZ 696, administered during T, P or TDM1 treatment, reduces in vitro anticancer drugs-related cardiotoxicity, more efficiently respect to Valsartan (V). We used our in Vitro model, the H9C2 rat cardiomyoblasts, treated with 200 nM of T, P or TDM1 for 3 days, and then treated in the absence or presence of 10 µM of LCZ 696 or V for additional 3 days.

Our results show that LCZ 696 is superior respect to V in the reduction of the cardiotoxic effects of T, P and TDM1, when administered to cultures of H9C2 cardiomyoblasts after antineoplastic treatments.

Indeed, LCZ 696 was significantly more effective than V in reducing T related cardiotoxicity, increasing cell viability of 25 % more, respect to V (p<0.001). LCZ 696 is more strong in the reduction of P related toxicity, increasing cell viability of 35% more respect to V, with p<0.001. And finally, again more effective than V in reducing TDM1 toxicity, increasing cell viability of 10 % (p<0, 05).