Considering the versatile functions of m6A in various physiological processes, it is thus not surprising to find links between m6A and numerous human diseases; many originated from mutations or single nucleotide polymorphisms (SNPs) of cognate factors of m6A. The linkages between m6A and numerous cancer types have been indicated in reports that include stomach cancer, prostate cancer, breast cancer, pancreatic cancer, kidney cancer, mesothelioma, sarcoma, and leukaemiaC-MYC(MYC) was among of the earliest described human oncogenes identified and is now recognized as the primary driver in oncogenic transformation and maintenance of cancer gene expression programs in a broad spectrum of cancer types where cells become “addicted” and dependent on MYC for survival. MYC transcript stability is coordinately regulated by RNA-binding proteins that both positively and negatively affect its half-life. Several RBPs interacting with m6A-modified RNA become upregulated in cancer, and are required for cellular growth, survival and invasion of cancer cells. Thus, Myc regulates cellular function and survival in part by modulating RNA metabolism and is itself controlled posttranscriptionally by RBPs.There have been conflicting findings regarding the function of YTHDF2 in cancer. For example, loss of YTHDF2 sensitizes acute myeloid leukemia (AML) cells to TNF-induced apoptosis, while overexpression of YTHDF2 in hepatocellular carcinoma (HCC) represses cell proliferation and growth by destabilizing EGFR mRNA [9, 10]. Moreover, the direct YTHDF2 target RNAs have yet to be defined in the mammary epithelial or in human breast cancer. It is unknown if the mechanism in other cancer types may be attributed to YTHDF2-Prss23 regulation. Existing art includes US20100104501A1 patent, characterizing Prss23 as a biomarker, therapeutic and diagnostic target. The invention involves compounds which bind to and/or inhibit the activity of PRSS23, which is the opposite of what we have determined is required to trigger apoptosis in Myc-dependent cancer.There are no current findings suggesting intervention of the YTHDF2-Prss23 binding interaction as a cancer therapeutic.

While splice modulators have entered clinical trials, limited clinical efficacy in splicing factor mutation-driven malignancies, such as acute myeloid leukemia, has remained a challenge. There is a pressing unmet medical need for developing potent small molecule splice modulators for the treatment of a broad array of malignancies characterized by splicing deregulation.  However, the inability to practically access gram-scale lead molecules with viable pharmacological properties continues to hinder their application.

Bioorthogonal ligations encompass coupling chemistries that have considerable utility in living systems. Among the numerous bioorthogonal chemistries described to date, cycloaddition reactions between tetrazines and strained dienophiles are widely used in proteome, lipid, and glycan labeling due to their extremely rapid kinetics. In addition, a variety of functional groups can be released after the cycloaddition reaction, and drug delivery triggered by in vivo tetrazine ligation is in human phase I clinical trials. While applications of tetrazine ligations are growing in academia and industry, it has so far not been possible to control this chemistry to achieve the high degrees of spatial and temporal precision necessary for modifying mammalian cells with single-cell resolution.

NK cells possess a native ability to kill tumors and virally infected cells without prior antigen priming. Furthermore, NK cells can be administered to patients across HLA allotypes, unlike T cells which require HLA matching to avoid graft-versus-host disease. Many trials utilizing adoptive transfer of allogeneic NK cells demonstrated complete remissions in patients with acute myelogenous leukemia (AML) who are refractory to standard chemotherapy. Another recent clinical study demonstrated effective treatment of lymphoid malignancies using allogeneic CAR-expressing NK cells, with minimal side effects. Thus, NK cells possess a number of advantages over T cells that enables them to be used as safe, effective, “off-the-shelf” adoptive cell therapy product to treat diverse malignancies. Antibody-dependent cellular cytotoxicity (ADCC) is a key pathway that mediates natural killer (NK) cell cytotoxicity against antibody-opsonized target cells. This process helps mediate the therapeutic efficacy of anti-tumor antibodies. On NK cells, ADCC occurs via engagement of antibody-coated target cells with activating receptor leading to proinflammatory cytokine upregulation, degranulation, and target cell death. Upon cellular activation, the     is cleaved from the NK cell surface. Cleavage of the ectodomain prevents further antibody binding and signaling, which dampens NK cell activity. Blocking activation-induced cleavage has been previously demonstrated to augment ADCC activity and provides a novel strategy to improve efficacy of therapeutic antibodies in combination with adoptive transfer of engineered NK cells. 

One of the main problems in using immune checkpoint inhibitors (e.g. PD-L1/PD-1/PD-L2/CTLA4) as a cancer treatment is that there is a large percentage of patients (~60-70%) who do not respond to the treatment or become resistant to it. Researchers all over the world are looking for ways to increase response to immunotherapy in this large population of patients, such as identifying new signaling pathways and/or new targets involved in this process as well as identifying synthetic molecules that can modulate the functions of those pathways and targets.

Pancreatic cancer is an aggressive disease with limited treatment options and a high mortality rate. Pancreatic cancer is the 3rd leading cause of cancer death in the United States; despite some recent advances in systemic therapy, survival remains dismal in large part due to its profound drug resistance and its propensity for early metastasis. Typically, diagnosis of pancreatic cancer occurs only with advanced stages of the disease since there are currently no early markers for detection. Individuals with pancreatic cancer have a poor prognosis due to the late diagnosis, the extent of metastasis, and ineffective treatments. Survival rates are dismal and pancreatic cancer is not typically responsive to radiation and chemotherapy. An alternative approach for the treatment of pancreatic cancer as well as the design of a new class of therapeutics that can be used to treat this devastating disease is an immediate unmet medical need.

Rho-family small (~21kDa) GTPases are essential for regulation of numerous cellular functions. There are 20 members of the Rho family in mammals, of which four (Rac1, Rac2, Rac3, RhoG) belong to the Rac subfamily. Each Rac GTPase functions as a molecular switch by cycling between an active GTP-bound form and an inactive GDP-bound form. In addition to their normal cellular functions, Rac GTPases contribute to cancer development as downstream effectors of growth factor receptor signaling and oncogenic mutations in the Ras pathway. Rac GTPases represent attractive targets for therapy in hematologic cancer, however direct targeting of small GTPases has proved difficult and largely ineffective. A thorough understanding of the diverse mechanisms controlling Rac activation in cancer will therefore be essential towards identifying new therapeutic avenues and improving outcomes in patients One insight into the regulation/activation of the Rac GTPases involves examining Ras proteins and their signal transduction pathways since mutations that produce abnormally active Ras proteins are found in 30% of all human cancers. Moreover, after activation, RAS signaling is mediated through interaction with RAS-binding domains or through the domain RAS association (RA), transmitted to downstream effectors. Notably, many downstream effectors are oncogenes or tumor suppressor genes that are mutated or silenced in cancers independently of RAS. Ras proteins are involved in Ras association domain-containing protein 2 (RASSF2) and it has recently been shown that in Acute myeloid leukemia cells with low expression of RASSF2 are more resistant to pharmacological inhibition of Dedicator of cytokinesis protein 2 (DOCK2), a guanine nucleotide exchange factor (GEF). Acute myeloid leukemia cells with high expression of RASSF2 are sensitive to pharmacological inhibition of DOCK2.

Human Ubiquitin-like modifier-activating enzyme 7 (UBA7) is a protein is involved in protein modification, specifically involving the pathway for protein ubiquitination. The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. UBA7  encodes a member of the E1 ubiquitin-activating enzyme family. Moreover, ubiquitination and ubiquitin-like post-translational modifications (PTMs) regulate activity and stability of oncoproteins and tumor suppressors. Biomarkers are very important as companion diagnostic tools to guide clinical practice in treating human cancers, especially for targeted therapies. In the era of precision medicine, it is important for development companion diagnostic tools that can guide clinical practice for treating human cancers using targeted therapies.

The existing CAR-engineered T cell-based (CAR-T) therapy represents one of the most successful immunotherapy approaches developed in recent years. Most CAR-T cell therapy has been used clinically to treat hematological malignancies by targeting the B cell-specific antigen, CD19. However, this approach is not without limitations due to toxicities such as by neurotoxicity or cytokine release syndrome. Additionally, CAR-T cells function only as autologous cells due to graft-versus-host disease that would develop if cells were obtained from another person. Therefore, CAR-T cells must be produced on a patient-specific basis. NK cells, on the other hand, function as allogenic cytotoxic effector cells that do not have to be utilized on a patient-specific basis and are proven to be less toxic since they do not cause cytokine release syndrome, neurotoxicity, or graft-versus-host disease. For these reasons, CAR-engineered NK (CAR-NK) cells have increasingly attracted interest as an alternative CAR-cell therapy. However, there exist other unmet challenges. Targeting CAR-based therapies against solid tumors has been challenging due to the lack of truly tumor-specific antigens as most targets are shared by non-malignant cells and can cause toxicity due to “on-target, off-tumor” effects.” A fine-tunable CAR therapy is useful to better identify and target tumors while limiting this toxicity.

The National Center for Advancing Translational Sciences and Genetic and Rare Diseases Information Center characterizes Pigmented villonodular synovitis (PVNS) as a rare disease estimated to occur in ~ 5-6 people out of 100,000. This locally invasive tumor most often occurs in younger adults and causes severe damage to joints. The first line of treatment is surgery but at least 50% of patients require multiple surgeries over many years due to re-growth of the tumor.

HRas is a member of the Ras family of GTPases, which function as key regulatory proteins in cell differentiation, proliferation, and survival. Mutations in HRas are associated with several cancers, as well as Costello syndrome, a severe congenital disorder for which there is no cure. Therefore, there is significant interest in developing therapeutics which target HRas signaling. However, Ras proteins are challenging to target

Transgenic mouse models that develop spontaneous mammary adenocarcinomas have proven valuable in revealing molecular mechanisms underlying tumorigenesis and metastasis . Models target specific pathways depending on the transgene being expressed under the control of the mouse mammary tumor virus long terminal repeat (MMTV-LTR) or whey acid protein (WAP) mammary gland promoters and thereby replicate genetic defects in subsets of human tumors.

Brief description not available

Brief description not available

The neuronal ceroid lipofuscinoses (NCLs), commonly grouped together as Batten disease, are the most common neurodegenerative lysosomal storage diseases of the pediatric population. No cure for NCL has yet been realized. Current treatment regimens offer only symptomatic relief and do not target the underlying cause of the disease. Although the underlying pathophysiology that drives disease progression is unknown, several small molecules have been identified with diverse mechanisms of action that provide promise for the treatment of this devastating disease. On this point, several researchers have reported the use of potential drugs for NCL patient lymphoblasts and fibroblasts, along with neurons derived from animal models of NCL disease. Unfortunately, most of these studies were inconclusive or clinical trials or follow-up results were not available. High concentrations employed and toxicity of the small molecules are clear disadvantages to the use of some of the corresponding derivatives as potential drugs. To circumvent these effects, development of nontoxic alkyl cysteines would be useful for the non-enzymatic and chemo-selective depalmitoylation of S-palmitoyl proteins, which hold good promise as an effective treatment for neuronal ceroid lipofuscinoses.

Pancreatic cancer is an aggressive disease with limited treatment options and a high mortality rate. Pancreatic cancer is the 3rd leading cause of cancer death in the United States; despite some recent advances in systemic therapy, survival remains dismal in large part due to its profound drug resistance and its propensity for early metastasis. Typically, diagnosis of pancreatic cancer occurs only with advanced stages of the disease since there are currently no early markers for detection. Individuals with pancreatic cancer have a poor prognosis due to the late diagnosis, the extent of metastasis, and ineffective treatments. Survival rates are dismal, with a one-year survival rate of 25% and a 5-year survival rate of 6%. Currently, approximately 20% of pancreatic cancer patients are able to undergo the Whipple procedure; this surgical procedure involves removal of the affected portion of the pancreas, leading to an increased survival rate. However, the remaining 80% of pancreatic cancer patients cannot undergo this treatment because their tumors or the extent of metastasis are too severe. In addition, pancreatic cancer is not typically responsive to radiation and chemotherapy. An alternative approach for the treatment of pancreatic cancer is a complete pancreatectomy followed by continual supplementation with digestive enzymes and insulin. Thus, more effective drugs are needed to increase the survival rate of pancreatic cancer patients. Targeting RORγ may lead to the design of a new class of therapeutics that can be used to treat this devastating disease.

Uveal melanoma commonly known as ocular or choroidal melanoma, is a rare cancer of the eye. It is an intraocular malignancy that arises from melanocytes of the choroid, ciliary body, and iris of the eye. Ocular melanoma is diagnosed in approximately 2,000-2,500 adults annually in the United States. In both the U.S. and Europe, this equates to about 5 - 7.5 cases per million people per year and, for people over 50 years old, the incidence rate increases to around 21 per million per year. While the primary tumor is highly treatable, about half of the patients will develop metastasis —typically to the liver. Metastatic disease is universally fatal. While traditional staging methods such as tumor size and location, still play a role in assessing metastatic risk, they are rarely used to individualize patient management plans. Newer methods include chromosomal gene expression analysis, yet these methods have their technical limitations. Clearly, what is needed is a better, cheaper and reproducible prognostic test.

Immune checkpoint inhibitors, such as antibodies that block negative regulators of T-cell activation (such as CTLA4 and PD-1/PD-L1), have transformed cancer treatment. However, even in metastatic melanoma and non-small cell lung cancer (NSCLC), malignancies that are highly responsive to immune checkpoint inhibitors (ICI), response rates rarely exceed 40%. Not only that, many common malignances, such as prostate cancer and pancreatic ductal adenocarcinoma, are ICI refractory but causes of treatment failure are largely unknown. It is known though that oxaliplatin triggers a form of cell death that is thought to be immunogenic, whereas the chemical analogue cisplatin does not trigger the same form of immunogenic cell death.   Recent clinical trials have shown that immune checkpoint inhibitors responsiveness is significantly augmented by combining PD-1 signaling inhibitors with platinoid chemotherapeutics. Such results have led to approval of immune checkpoint inhibitors + platinoid combination therapy in NSCLC but the basis for this synergism has not been determined.

RNA-editing proteins are an important class of proteins that regulate key steps in post-transcriptional RNA processing. One of the most common and best characterized is the Adenosine-to-Inosine editing (A-to-I editing) process. The cell translating machinery recognizes inosine as guanosine and A-to-I editing is accomplished by adenosine deaminase acting on RNA (ADAR) enzyme family that includes ADAR1, ADAR2, and ADAR3. While ADAR3 appears to inhibit ADAR2 editing within coding regions, ADAR1 edits primarily within double stranded RNA (dsRNA) loops formed by inverted primate-specific Alu repetitive elements. Atypical RNA editing can result in the alteration of non-coding RNAs such as miRNAs which can be present in different cancers and play a role in their development.  

Stimulator of interferon genes (STING) is known to be a central mediator of innate immunity. It is a 379 amino acid protein expressed in various endothelial and epithelial cell types as well as in hematopoietic cells such as T cells, macrophages and dendritic cells. STING is naturally activated by aberrant DNA species via formation of native cyclic dinulcleotides (CDNs) in cytosol of the cell. When stimulated STING induces the expression of type I interferon (IFN), cytokines and T cell recruitment factors that result in the activation of macrophages and dendritic cells, innate effector cells such as natural killer (NK) cells and priming of tumor specific T cells. Recent studies have shown that the STING pathway is essential for radiation induced and spontaneous natural antitumor T cell responses. Tumor cells often induce an immunosuppressive microenvironment favoring cancer development. Targeting STING pathway by using TING agonists to produce IFNs for enhancing antitumor immune response may provide an alternative strategy for the improvement of cancer immunotherapy.

Primary liver cancer, with the majority being hepatocellular carcinoma (HCC), is now the second leading cause of cancer mortality and the fifth most common cancer worldwide, claiming approximately 800,000 life every year. HCC is a chemotherapy resistant tumor with limited treatment options including surgical resection, liver transplantation and local ablation at the early stages. Sorafenib, a multi-kinase inhibitor, remains a first-line systemic drug for advanced HCC even with poor outcomes, and similar low therapeutic benefits were reported for regorafenib, lenvatinib, and cabozantinib. Over 100 clinical trials that tested other compounds or approaches have failed to show therapeutic benefit to HCC patients. Immunotherapy by blocking inhibitory pathways in T lymphocytes, such as the PD-L1/PD-1 axis, is being widely tested in various solid tumors. Notably, this emerging therapeutic approach is already in clinical trials for advanced HCC in multi-centers around the globe. Two latest reports on open-label, non-randomized, phase 1/2 trials with pembrolizumab or nivolumab indicated manageable safety in advanced HCC patients with or without prior sorafenib treatment, albeit with very limited therapeutic benefits observed so far. The outcome of immunotherapy for liver cancer can be compounded by the unique immunotolerant microenvironment in the liver. A variety of clinical trials are ongoing to evaluate combination of immune checkpoint inhibitors or with other drugs, without clear justification or support by preclinical data.

Natural killer (NK) cells are a key component of the innate immune system and are involved in early defense against viruses and cancer cells. NK cells have the ability to lyse cells without prior sensitization  and therefore are the subject of intense interest to be potentially used as immunotherapeutic targets to treat cancer. The crucial element for using NK cells in immunotherapy is the ability to control the signaling and activation pathways. Recent work has shown that the cytokine-inducible SH2-containing protein (CIS), encoded by the Cish gene, can act as a checkpoint in NK activation by inhibiting IL-15 signaling, a major upregulator of NK cell activity. Furthermore, deletion of the Cish gene has been shown to increase the sensitivity of NK cells to IL-15, resulting in mice that are resistant to experimental metastasis.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is currently the third- leading cause of cancer death in the United States, and is predicted to be the second such cause by 2020. The current 5-year survival rate of PDAC is ~8%. Factors that contribute to this high death rate include the early, asymptomatic phase of the disease, such that at the time of diagnosis, many patients have locally advanced or metastatic disease. Surgical resection, the only curative treatment, is feasible in <20% of patients. Chemotherapy of PDAC has had limited impact. The EGFR inhibitor erlotinib is the only approved targeted therapy and produces minimal clinical benefit. New, effective treatments of pancreatic cancer are thus a major, unmet medical need. G protein-coupled receptors (GPCRs), the largest family of cell signaling receptors (~3% of the human genome), are seven transmembrane receptors that respond to numerous types of extracellular signals and regulate many physiological processes. Emerging evidence implicates GPCRs in cancer: certain GPCRs have increased expression in tumors and are involved in cancer initiation and/or progression. GPCRs can contribute to fibroblast myofibroblast conversion and increases in cellular cAMP (a second messenger for certain GPCRs) can blunt the myofibroblastic phenotype. Little is known regarding the role of GPCRs in pancreatic cancer-associated fibroblasts (CAFs).

Metastasis is a complex process in which cancer cells migrate from the primary tumor, invade into the vasculature, and travel to distant parts of the body to establish secondary tumors. Cells with a greater metastatic potential have a proclivity for leading migration away from the primary tumor. Progress in identifying cells primed to metastasize and in assessing metastatic risk has been slow. This may be due in part to the lack of consistent molecular prognostic markers between cancer types and significant heterogeneity in metastatic potential within the tumor. Furthermore, not all tumors are metastatic and determining the metastatic proclivity of single tumor cells remains a major challenge. Another looming scientific question is estimating the metastatic “potential” because conventional techniques, e.g., Immunohistochemistry (IHC) are not capable of this and only molecular imaging can resolve these issues. So far, improved imaging platforms have helped detect established metastases and assessed tumor cell properties such as surrogate markers of metastatic potential. However, single cell-based assays to measure the dynamic pro-metastatic signaling programs that contribute to the 'potential' for metastasis remains a Holy Grail.

Metastasis is a complex process in which cancer cells migrate from the primary tumor, invade into the vasculature, and travel to distant parts of the body to establish secondary tumors. Cells with a greater metastatic potential have a proclivity for leading migration away from the primary tumor. Progress in identifying cells primed to metastasize and in assessing metastatic risk has been slow. This may be due in part to the lack of consistent molecular prognostic markers between cancer types and significant heterogeneity in metastatic potential within the tumor. However, all metastatic cells – independent of tumor type or heterogeneity within the tumor – must detach from the tumor, migrate through the surrounding tissue, and invade the blood stream. This process involves a significant change in adhesion, which can be quantified in a heterogeneous population of cancer cells.