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Neoantigen-specific antibodies for chemically directed immune targeting of KRAS tumors

UCSF scientists have discovered novel antibodies that can specifically and selectively recognize tumor-derived neoantigens. The antibodies can be used for IgG, BiTE or CAR-T-based targeted immunotherapy and small molecule-based directed immune targeting via combination therapy. This dual therapeutic approach has the potential to specifically recognize and treat KRAS (G12C) cancer cell populations with high specificity, significantly improve cancer treatment outcomes, and overcome risk of treatment resistance in patients.

A Tumorigenic Index to Determine Live Cancer Initiation and Prognosis

The incidence and mortality of liver cancer, mainly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), are increasing rapidly worldwide. Diverse risk factors for primary liver cancer have been identified, including infection of hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol abuse and non-alcoholic steatohepatitis (NASH) as well as intake of aflatoxin B1. Consistent with the complex and multifactorial etiologies, multi-omics analyses of human HCC and ICC samples have identified vast genomic heterogeneity, molecular and cellular defects, metabolic reprogramming, and subtypes of tumors as well as altered tumor microenvironment in the liver. However, it remains to be determined if any common molecular signatures in the transcriptomes exist for liver cancer, despite their considerable genomic heterogeneity. Furthermore, little is known about the kinetics and fashions, either gradual accumulation or dramatic transition, in generation of cell-intrinsic and -extrinsic signals that are intertwined to drive malignant transformation of hepatocytes and tumor initiation.

Computational Cytometer Based On Magnetically-Modulated Coherent Imaging And Deep Learning

UCLA researchers in the Department of Electrical & Computer Engineering have designed and built a computational cytometer capable of detecting rare cells at low concentration in whole blood samples. This technique and instrumentation can be used for cancer metastasis detection, immune response characterization and many other biomedical applications.

IFN-gamma Receptor On T Cell Immunotherapy

This invention identifies that tumor-specific T cells are susceptible to immunotherapy induced IFN-gamma toxicity in low tumor burden circumstances, and provides a novel method for rescuing those tumor-reactive T cells and anti-tumor immunity through disruption of IFN-gamma signaling.

Switchable Chimeric Antigen Receptor-Engineered Human Natural Killer Cells

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.

Use of Gene Therapy to Treat Joint Disease and Synovial Tumors

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.

Prevention Of Liver Disease By Preventing Degradation Of SRSF3

The global increase in obesity over the past few decades has caused a corresponding increase in NAFLD and its more severe form non-alcoholic steatohepatistis (NASH). Both NAFLD and NASH are associated with liver insulin resistance, non-alcoholic cirrhosis, and for the development of HCC. HCC is currently ranked as the fifth most common cancer worldwide and has a high mortality. It usually arises after years of liver disease and inflammation either due to chronic hepatitis B or C virus (HBV/HCV) infection, or alcoholic and non-alcoholic cirrhosis. SRSF3 is the smallest member of the SR protein family that function to promote RNA splicing by recruiting components of the spliceosome at constitutive and alternatively spliced exons. SRSF3 has also been ascribed a number of cellular functions including controlling cellular proliferation, as it is regulated during G1/S by the E2F transcription factor and controls the G2/M transition of immortal rat fibroblasts.  Recent findings demonstrating that loss of SRSF3 triggers metabolic changes, hepatic fibrosis, and increased liver inflammation that are all features of early liver disease. The loss of expression of SRSF3 in the liver leads to chronic liver damage, fibrosis and eventually to hepatocellular carcinoma (HCC). In fact, SRSF3 is reduced in samples of human HCC as well as NAFLD, NASH and cirrhosis. SRSF3 protein levels are controlled in part by the conjugation of SRSF3 to an ubiquitin-like protein NEDD8 on Lys11, which results in its degradation by the proteasome in response to stress.

Identification Of Pan-Cancer Small Cell Neuroendocrine Phenotypes And Vulnerabilities

UCLA researchers in the Department of Molecular and Medical Pharmacology have developed a classifier for the identification and treatment of small cell neuroendocrine cancers and small-round-blue cell tumors not previously identified.

Improvement To Retroviral Vectors Containing The Human Ubiquitin C Promoter

UCLA researchers in the Department of Molecular Biology have developed a lentiviral vector, “pCCLc-roUBC”, containing the cellular promoter from the human ubiquitin C gene (UBC), to improve transgene expression in retroviral vectors.

HRas Selective Depalmitoylating Drugs

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

A Microfluidic Single-Cell Pairing Array for Studying Cell-Cell Interaction in Isolated Compartments

Cell interactions are fundamental to biological processes. Microfluidics provides a reliable platform to study these intricate phenomena. The researchers have developed a microfluidic trapping array which efficiently pairs single cells in isolated compartments in an easy to operate manner to study cell-cell interaction, especially at single-cell level.

Improved Highly Potent Specific Human Kunitz Inhibitor of Fibrinolytic Enzyme Plasmin

UCLA researchers in the School of Medicine have developed mutant polypeptides of the tissue factor pathway inhibitor-2 (TFPI-2) Kunitz domain 1 (KD1), which can serve as potent inhibitors of fibrinolysis.

Gelatin Methacryloyl Based Microneedle

UCLA researchers in the Department of Bioengineering have developed gelatin methacryloyl microneedles (GelMA MN) for minimally invasive, sustained transdermal drug delivery.

Antitumor Activity Of Sd-101 Alone Or In Combination With A-Pd-1 Therapy In Tumors Resistant To Anti-Pd-1

UCLA researchers in the Department of Medicine have developed a novel antitumor treatment that works alone or in combination with anit-PD-1 therapy to target interferon signaling-deficient tumors or tumors with alterations in the antigen presentation machinery, that are resistant to anti-PD-1 therapy.

Brain-Specific Kinase Inhibition to Mitigate Systemic Toxicity

The goal of this invention is to overcome the challenges of previous approaches by selectively targeting treatments to the CNS without peripheral toxicity. Kinase inhibition is targeted to the central nervous system (CNS) by combining brain-permeable kinase inhibitors and a brain-impermeable blocking molecule.

Chimeric Kinase Inhibitors with Increased Activity

This invention describes newly generated kinase inhibitors that demonstrate enhanced and attenuated action over their parent kinase inhibitors. These molecules can be used alone but, when combined with novel blocking molecules, the action of these chimeric kinases can be targeted for action in the central nervous system (CNS).

TRM: Mouse Mammary Tumor Virus-PyMT Transgenic Mice

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.

NOVEL ANTIBODIES AGAINST EPHA2 FOR RESEARCH, DIAGNOSIS, AND TREATMENT OF CANCER

A novel monoclonal human antibody specific to the cell-surface exposed protein EphA2, which is over-expressed in many forms of cancer and is a validated therapeutic target.

TRM:Murine Pancreatic Cancer Cell Lines

Brief description not available

Strategy for in vivo Depalmitoylation of Proteins and Therapeutic Applications Thereof

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.

Hv1 Modulators and Uses

Researchers at UCI have engineered a class of Hv1 polypeptide modulators that selectively modulate Hv1 voltage gated channels while leaving other voltage gated channels unaffected. With no Hv1 modulators currently on the market, this class of Hv1 polypeptide modulators could provide solutions in birth control, autoimmune therapies, and tumor reduction.

Identification of a New Molecular Target and Methods for Treating Pancreatic Cancer

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.

Clinical Prognostication Test In Uveal Melanoma

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.

“Polyp-Print”: A Methodology To Identify Which Colon Polyps Are Likely To Proceed To Colorectal Cancers

Colorectal cancer (CRC) is the second leading cause of cancer deaths in men and women combined in the United States, according to the American Cancer Society. Every day, patients undergo routine screening colonoscopies around the world for assessment of their risk of CRC. CRCs always arise from precursor lesions, called polyps. Since most patients with polyps are asymptomatic, tracking these lesions through fecal occult blood, rectosigmoidoscopy and colonoscopy enables the suspicion, detection and removal of the lesion. Since 2000, colonoscopy has become the most important examination to track polyps and CRC. Nowadays, in the USA, one out of four colonoscopies aim to track polyps. Besides detecting polyps, their removal through endoscopic polypectomy has proved to be effective to reduce the incidence of this tumor. Anatomopathological analysis enables the histological classification of adenomas, and also allows checking for dysplasia or neoplasm, as well as vascular and/or lymphatic invasion. This assessment determines if polypectomy and/or mucosectomy were effective to heal the patient who presented with polyp or CRC, or if therapeutics will be necessary. Typically, screening colonoscopies begin at age 50, and are done every 10 years. If polyps are encountered, based on their size and number and location, the risk is determined to be high vs low (completely arbitrarily, with no molecular basis at all). Bottomline, right now, there is no way to tell which polyp will become a cancer and which will not. Hence, some patients may be receiving over Rx and some may be under Rx. Clearly, what is needed is an invention that can predict the timing and consequences of multiple host events during CRC initiation and progression.

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