RESEARCH

Dr. Lam is a medicinal chemistry and drug discovery consultant. He currently collaborates with Blumberg scientists in terms of drug discovery and jointly supervises Blumberg chemistry postdocs and visiting scientists.

Dr. Lam has 30 years of extensive experience in innovation in structure-based drug design, ADME, focused libraries, molecular recognition and nucleic acid therapeutics to deliver biopharma clinical candidates with novel profiles. He is responsible for the discovery of a total of eight clinical candidates. At Bristol Myers Squibb, Dr. Lam was the group leader/co-inventor responsible for the discovery of  Eliquis®/Apixaban, a novel Factor Xa anticoagulant recently launched on the market. Eliquis® is projected by analysts to be a transformational medicine with “block-buster” sales potential. Eliquis® was chosen as the “Best New Medicine of 2012” by Med Ad News. He and his team were awarded 2015 American Chemical Society Heroes of Chemistry Award for the discovery of Eliquis®. Dr. Lam is also the inventor of the novel cyclic urea class of HIV protease inhibitors that resulted in Mozenavir/DMP450. In Phase II clinical trial, Mozenavir was shown to be as efficacious as Merck’s Crixivan, but without the lipodystrophy side effect of Crixivan.

In recent years, he has been involved with antivirals (HBV capsid, surface antigen and cccDNA inhibitors, Dengue Fever inhibitors, HIV-DCSIGN blockers), antithrombotics (FXIa and FXa inhibitors as anticoagulants; P2Y1 and PAR4  antagonists as antiplatelet agents), PCSK9 antisense oligonucleotide (ASO) therapeutics, prodrugs and carbohydrates.

In the organic chemistry area, he is internationally known as the co-discoverer of the powerful copper-promoted Chan-Lam Coupling Reaction, a complementary reaction to the Nobel-prize winning Suzuki-Miyaura Coupling Reaction. Dr. Lam has authored 98 papers/reviews/book chapters, invented 36 patents/patent applications and presented 110 invited seminars worldwide

Sean Lam has a PhD and Masters in Industrial and Systems Engineering, Operations and Business Analytics from the National University of Singapore.  He is currently the Senior Data Science Manager of the Sing Health Services Research Centre (HSRC), overseeing a team of data scientists and analytics professionals for the enhancement of patient care and outcomes through health services research. Sean is also an Assistant Professor at the Signature Program in Health Services and Systems Research, Duke-NUS. He has more than 20 international publications, and won numerous awards from local and international research symposiums.

Cluster Dean / Associate Professor Head, Department of Pharmaceutical Education, Geomatika University College, Kuala Lumpur, WP Kuala Lumpur, Malaysia. He received the PhD in Department of Phytochemistry, The Open International University for Complementary Medicines – Srilanka in 2012. He established new drug information centre in Malaysia (GUC).

Major area of interests include Phytochemistry, Pharmaceutical Science and Pharmacy practice

Abstract

Signal Transducers and Activators of Transcription (STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation, survival, and angiogenesis. Among various STAT members, STAT3 is frequently overexpressed in tumor cells as well as tissue samples, and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells. I will briefly discuss the importance of STAT3 as a potential target for prostate cancer therapy and also provide novel insights into various classes of existing pharmacological inhibitors of this transcription factor that can be potentially developed as anti-cancer drugs.

Abstract:

Despite detection tests being developed for many cancers, there is no single test to identify cancer in general. We have developed such an assay. In this modified patented Comet assay, we investigated peripheral lymphocytes of 208 individuals: 20 melanoma, 34 colon cancer, 4 lung cancer patients 18 suspect melanoma, 28 polyposis, 10 COPD patients and 94 healthy volunteers. The natural logarithm of the Olive tail moment was plotted for exposure to UVA through different agar depths for each of the above groups and analysed using a repeated measures regression model. Response patterns for cancer patients formed a plateau after treating with UVA where intensity varied with different agar depths. In comparison, response patterns for healthy individuals returned towards control values and for pre/suspected cancers, were intermediate with less of a plateau. All cancers tested exhibited comparable responses. Analyses of Receiver Operating Characteristic curves, of mean log Olive tail moments, for all cancers plus pre/suspected-cancer versus controls gave a value for the area under the curve of 0.87; for cancer versus pre/suspected-cancer plus controls the value was 0.89; and for cancer alone versus controls alone (excluding pre/suspected-cancer), the value was 0.93. By varying the threshold for test positivity, its sensitivity or specificity can approach 100% whilst maintaining acceptable complementary measures. Evidence presented indicates that this modified assay shows promise as both a stand-alone test and as a possible adjunct to other investigative procedures, as part of detection programmes for a range of cancers. This test has been repeated with 900 individuals and responses remain equally predictive.

Plants are rich sources of antioxidants which mainly attributed to its components. Rosmarinus officinalis L and Tamarixaphylla are among herbal plants, with a long history of medicinal and culinary use. The modifying influence of leaves extract of both herbs were studied in experimental albino rats. Selected doses were chosen as radio protectors against Gamma [γ] radiation hazards. The experimental Westar rats were exposed to 5 Gry for 15 min before and after treatment with rosemary and tamarix extracts in a dose of 100 mg/kg/ b/ wt of each respectively. The treated animals were autopsied for collection of blood serum at days 1, and 15 post-irradiation. Results: A decrease in the hematological parameters and Glutathione level was registered in the positive irradiated control group. A recovery pattern were recorded in the pre and after treated groups. The whole hematological parameters were ameliorated back to the normal by day 15; as a significant elevation was achieved with groups treated with rosemary and tamarix extracts compared to irradiated one. An increment in the level of lipid peroxidation above normal was noted in serum of irradiated rats. This increment was significantly reversed upon treatment by rosemary and tamarix extracts. Moreover interlukin 6 levels were highly modified in the treated groups. The whole results were confirmed Histologically by the improvement seen in the (PCNA) proliferating cell nuclear antigen )level antigen.Conclusion:Considering these biochemical and histological results, the present study suggests the significant importance for both herbs with the superior role of rose marry as a magnificent radio modifier herb.

Background:  Intestinal metaplasia  (Incomplete type 111) of the stomach has been shown to increase the relative risk of gastric cancer by a factor of 4.58. Survival following curative surgery (R0) for early gastric cancer has increased and, therefore showed the need for endoscopic surveillance for local recurrence.

Objective:  Since at present there are no other recognized good markers for gastric dysplasia or cancer, we reviewed the literature on  intestinal metaplasia (IM) of the stomach to ascertain whether residual premalignant (type 111) IM may predispose to anastomotic recurrence of gastric cancer.

Method: Electronic searches of the Medline (PubMed) database, Cochrane library and science citation index were performed to identify original published studies on IM, gastric cancer and anastomotic recurrence. Endoscopic features of early gastric cancer (EGC) or IM that exist on a specific location on the gastric remnant such as at the anastomosis and non-anastomosis sites were characterized.

Results:  Most recurrent cancers (a cancer developing  on the anastomosis  site  < 10 years after surgery for gastric malignancy) are advanced, undifferentiated and of the diffuse type. Most residual cancers ( a cancer developing < 10 years after surgery for gastric malignancy except at the anastomosis site)  are of the intestinal type and well differentiated. Incomplete IM (type 111) with type 11b sialomucins and sulphomucin staining demonstrated in the resected specimen is the appropriate IM that requires subsequent endoscopic follow-up.

Conclusions:  Endoscopic surveillance following curative surgery for early gastric cancer should not only be focused on the anastomotic site as in benign disease, but also on the rest of the gastric remnant as residual cancer may be missed.  In addition, the role of H. pylori  eradication therapy in preventing anastomotic recurrence or a new primary by attenuating the chronic gastritis-metaplasia- dysplasia -carcinoma sequence should not be underestimated.

Abstract:

Cancers of oral cavity is a major health concern worldwide with highest incidence in India. Unfortunately, in India, almost 2/3 of the oral cancer cases are diagnosed only in the advanced stage of the disease making it difficult to treat and decreasing the chances of survival. Therefore, it is essential to develop novel biomarkers for the better management of this deadly disease. In the current study, a novel tumor necrosis factor alpha induced protein 8 (TNFAIP8 or TIPE) protein family was examined for its therapeutic and prognostic potential against oral cancer. The protein family comprises of four proteins namely, TNFAIP8 (TIPE), TNFAIP8L1 (TIPE1), TNFAIP8L2 (TIPE2) and TNFAIP8L3 (TIPE3). Immunohistochemical analysis revealed that expression of TIPE, TIPE2 and TIPE3 were upregulated and levels of TIPE1 were downregulated in squamous cell carcinoma (SCC) tissues compared to the normal tissues. In addition, treatment of oral cancer cells with tobacco and related carcinogens resulted in a significant upregulation of TIPE, TIPE2 and TIPE3 and downregulation of TIPE1 protein. Moreover, knockout of TIPE proteins was found to modulate the cancer hallmarks associated with oral cancer such as cancer cell survival, proliferation, colony formation and migration. Further, while TIPE, TIPE1 and TIPE2 proteins exhibited their activity through regulation of Akt/mTOR signaling cascade, TIPE3 acted through an Akt-independent mTOR/STAT3 pathway. Taken together, our results suggest that the TIPE proteins can be used as drug targets for the treatment of oral cancer.

Abstract:

Breast cancer is the most commonly diagnosed cancer and second leading cause of cancer death in women. Cancer metastasis, resistance and recurrence hinders successful treatment for breast cancer. Identification of breast cancer stem cells as the chemoresistant and tumor initiating population represents an important milestone in approaching anticancer therapies. Targeting this minor subpopulation of chemo- and radioresistant stem-like cells, termed as the cancer stem cells (CSCs) and their ultimate eradication could significantly enhance clinical outcomes. CSCs are resistant to conventional cytotoxic agent and radiology therapy. They also display aggressive invasion phenotype. Cancer stem cells share core signaling pathways with normal somatic stem cells, but also exhibit distinctions that provide important clues into useful therapeutic targets. Aberrant regulation of Wnt signalling by autocrine mechanism is reported which promote the CSC proliferation and survival from the chemotherapy. In this study we observed that ursolic acid, a natural compound derived pentacyclic triterpenoid, had a potent inhibitory effect on breast cancer cells by not only inducing apoptosis but also by reducing the stemness properties and decreasing the CSC population. As self-renewal and chemoresistant properties of CSCs are linked to the Wnt ß-catenin pathway, we hypothesized that the observed effects of these compounds on CSC could be through modulating this pathway. Our results clearly suggests that plant derived compounds like UA are capable of targeting cancer stem cells and exert their effect by antagonizing the Wnt- ß-catenin pathway.

Celastrol is a highly investigated anticancer moiety. It is a pentacyclic triterpenoid, isolated several decades ago with promising role in chemoprevention. Celastrol has been found to target multiple proinflammatory,angiogenic and metastatic proteins. Inhibition of these targets results in significant reduction of cancer growth, survival and metastasis.