Root Cause Of Cancer Research Articles

Abstract A040: Suppressing the cytomatrix elastic solid phase of cytoplasm will eliminate the root cause of cancer

Abstract The Warburg effect, the increase of glucose uptake rate and lactate production, is a tremendous metabolic switch, a prominent cancer hallmark, and a century-old mystery. We recently solved an age-old problem of biochemistry, how myriad diverse chemical reactions coincide in the cell, by chemically separating elastic solid (cytomatrix) and viscous fluid (cytosol) phases of cytoplasm (iScience, 2023, PMID:36824274) that can elucidate a role of the Warburg effect in tumors. Biochemical reactions within the cytoplasm are catalytic and performed by enzyme complexes. Catalytic complexes are immobilized on the solid platform, and the cytomatrix physically separates them from each other, but the substrate delivery mechanisms have remained unknown. Using the multiomic approach, we found that cytomatrix proteins actomyosins are responsible for cellular micromechanics and cytosolic motion. Cytosolic motion delivers substrates to catalytic complexes. Cytomatrix micromechanics requires energy maintained by mitochondrial respiration in physiological conditions. However, due to mutational and epigenetic alterations, malignant cells need additional energy to stir biochemical processes. Actomyosin and actin-binding and regulating proteome, a structural base of the cytomatrix and primary motor proteins, exploits aerobic glycolysis to meet the energy demand of cytomatrix, just as muscle fiber utilizes the aerobic glycolysis during intense exercise. Therefore, synchronizing energy output for cytomatrix micromechanics is a limiting step for the malignant transformation involving the Warburg effect. Unless mutations coalesce with the increased energy production for cytomatrix mechanics, potential cancer may only survive in the quiescent state (or benign), or it will be eliminated. Cancer development appears to be a two-sided coin relying on both the mutation and the energy demand, suggesting that not everyone gets cancer with the same mutation without the involvement of aerobic glycolysis. By uniting the Warburg effect with the cytomatrix micromechanics and genetic and epigenetic alterations, our concept of cancer development better explains the transformation of healthy cells to malignant cells and malignant cell resistance to therapy and recurrence. Revealing the cytomatrix allowed us to find its practical application. We developed technology that works on the cytomatrix level and can improve cancer treatment and prevent tumor recurrence. Suppression of the cytomatrix activity will inhibit cancer resistance and recurrence and increase the efficiency of the current anticancer therapy. It is impossible to know if cancer will return after treatment. Cancers come back when small numbers of malignant cells can remain in the body after treatment. These cells are too rare to find with current tests. We have developed a method to help detect this small number of malignant cells. Our fast and sensitive method can isolate malignant cells from a frozen biopsy about 10 – 20 mg weight. Thus, revealing the cytomatrix opens a new chapter in cancer research and therapy. Citation Format: Tattym E. Shaiken. Suppressing the cytomatrix elastic solid phase of cytoplasm will eliminate the root cause of cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A040.

Promising directions in the development of new vaccines against papillomavirus infection

Papillomavirus infection is one of the most common viral infections worldwide. Highly oncogenic types of human papillomavirus (HPV) are the root cause of cancer of the cervix, vulva, vagina, genitals in men, anal cancer, as well as cancer of the oropharyngeal region. Currently, three HPV vaccines have been registered and successfully used in Russia: divalent (HPV types 16, 18) and quadrivalent (HPV types 6, 11, 16, 18). In the countries of America and Europe, a nine-valent vaccine is available, which contains nine types of HPV (6, 11, 16, 18, 31, 33, 45, 52, 58). These vaccines are preventive, have high immunogenicity and induce the production of specific antibodies. The action of preventive vaccines is aimed at creating specific humoral immunity to the capsid proteins of the virus, which leads to the prevention of HPV infection. Nevertheless, there are no specific medicines on the pharmaceutical market aimed at treating an already established pathology.
 Currently, active development of HPV vaccines with both preventive and therapeutic effects is underway. Candidates of therapeutic HPV vaccines undergo various stages of research. Experimental vaccination systems on animal models provide encouraging results. If preventive and therapeutic HPV vaccines prove to be effective in patients as well as in animal models, then pillomavirus infection and related malignant diseases can be controlled by vaccination.

Deregulation of All-Trans Retinoic Acid Signaling and Development in Cancer.

Cancer stem cells are the root cause of cancer, which, in essence, is a developmental disorder. All-trans retinoic acid (ATRA) signaling via ligand-activation of the retinoic acid receptors (RARs) plays a crucial role in tissue patterning and development during mammalian embryogenesis. In adults, active RARγ maintains the pool of hematopoietic stem cells, whereas active RARα drives myeloid cell differentiation. Various findings have revealed that ATRA signaling is deregulated in many cancers. The enzymes for ATRA synthesis are downregulated in colorectal, gastric, lung, and oropharyngeal cancers. ATRA levels within breast, ovarian, pancreatic, prostate, and renal cancer cells were lower than within their normal counterpart cells. The importance is that 0.24 nM ATRA activates RARγ (for stem cell stemness), whereas 100 times more is required to activate RARα (for differentiation). Moreover, RARγ is an oncogene regarding overexpression within colorectal, cholangiocarcinoma, hepatocellular, ovarian, pancreatic, and renal cancer cells. The microRNA (miR) 30a-5p downregulates expression of RARγ, and miR-30a/miR-30a-5p is a tumor suppressor for breast, colorectal, gastric, hepatocellular, lung, oropharyngeal, ovarian, pancreatic, prostate, and renal cancer. These complementary findings support the view that perturbations to ATRA signaling play a role in driving the abnormal behavior of cancer stem cells. Targeting ATRA synthesis and RARγ has provided promising approaches to eliminating cancer stem cells because such agents have been shown to drive cell death.

Viscoelastic and Viscoplastic Glucose Theory (VGT #22): Applying the Concepts of Viscoelasticity, Viscoplasticity and Perturbation Theories to Predict Cancer Risk Percentages using the overall Lifestyle Scores and Calculated Cancer Risk Change Rates with Corresponding Lifestyle Scores as the Respective Viscosity Factors along with Studying the Relationship between Cancer Risks and Diabetic Glucoses Based on the GH-Method: Math-Physical Medicine (No. 601)

Viscoelastic and Viscoplastic Glucose Theory (VGT #22): Applying the Concepts of Viscoelasticity, Viscoplasticity and Perturbation Theories to Predict Cancer Risk Percentages using the overall Lifestyle Scores and Calculated Cancer Risk Change Rates with Corresponding Lifestyle Scores as the Respective Viscosity Factors along with Studying the Relationship between Cancer Risks and Diabetic Glucoses Based on the GH-Method: Math-Physical Medicine (No. 601)

A Paradigm Shift in Oncology and Its Treatment: A Review

The present standard therapies for cancer, surgery, anti-cancer drugs, and radiotherapy, have major issues in advanced cancers especially. It is unlikely that they will cure the disease permanently. They require huge medical expenditure and the adverse side effects accompanying them put many patients in anguish. These problems may be considered as a result of initiating treatments without considering the root cause of cancer: "the change in energy metabolism." Tumor cells have unique metabolic characteristics, and henceforth cancer can be treated as a metabolic disease and be interfered at different stages of cell metabolism. Cancer, also being characterized by an immunological imbalance, focusing on targeting, involving, and regulating cancer-associated immune cells in the tumor microenvironment (TME) with nanomedicines can potentially become a great tool to stop cancer. Stem cells and mAbs have the capability to come handy in targeting the immune system, which demands more clinical research to be done.

Abstract P242: Preclinical efficacy landscape of the pan-CLK/DYRK inhibitor Cirtuvivint (SM08502)

Abstract A monumental challenge facing cancer therapy is the vast mechanistic diversity of tumors among and even within cancer patients. This severely limits the number of patients that respond to any given therapy and the durability of responses that do occur. Deep phenotypic profiling of almost 9000 patient samples indicates perturbation of alternative pre-mRNA splicing (AS) is often a root cause of cancer. This offers an extraordinary opportunity to restore health through normalization of AS in diseased tissue. The bottleneck to progress has been finding and drugging the right targets. The CLK/DYRK kinases modulate AS efficiency and specificity, and therefore, targeting them offers the potential to address this bottleneck. The isoquinoline cirtuvivint is a potent ATP-competitive inhibitor of the Cdc2-like kinases (CLK1-4) and the dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1-4), with activity against only a minimal number of the remaining members of the CMGC-family kinases or the kinome as a whole. Cellular target engagement assays indicated biological IC50s below 0.06 μM across the CLK/DYRK target class. Thus, cirtuvivint has utility for robust chemical evaluation of the overarching contribution of CLK/DYRK family activity to tumor biology in general and context- dependent AS in particular. To help assess the breadth and depth of CLK/DYRK dependencies in human cancers, the consequences of pan-CLK/DYRK inhibition on growth and survival of 154 cancer cell line models, 46 PDX models, and 43 CDX models were tested. EC50s in cell viability assays ranged from 0.014 to 0.73 μM in culture with strong effects observed in subsets of cell lines across all lineages tested. Molecular profiles associated with high sensitivity to cirtuvivint included somatic mutations in the RBM10 splicing factor. Tumor growth inhibition assays with daily dosing at exposures about 2X below the MTD resulted in significant disease control (≥75% TGI) in 15/46 PDX and 18/43 CDX models. Together, these results indicate broad cancer relevance, at least in the preclinical setting, and are consistent with a common reliance on CLK/DYRK-dependent alternative splicing among otherwise highly mechanistically heterogeneous disease. Citation Format: Carine Bossard, Emily Creger, Elizabeth A. McMillan, Carsten Merkwirth, Maureen Ibanez, Deepti Bhat, Josh Stewart, Brian Eastman, Chi-Ching Mak, Vishal Deshmukh, Michael A. White. Preclinical efficacy landscape of the pan-CLK/DYRK inhibitor Cirtuvivint (SM08502) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P242.

Paradigm shift in cancer treatment: Cancer treatment as a metabolic disease – fusion of Eastern and Western medicine

Current standard therapies for cancer, including surgery, anti-cancer drugs, and radiotherapy, are thought to contribute to the improvement in the survival rates of cancer patients. However, such standard therapies have 3 major problems: in advanced cancers, it is unlikely that standard cancer treatments will cure the disease; adverse side effects that accompany standard cancer treatments put many patients in distress; and a large amount of medical expenditure is required for new and expensive anti-cancer drugs. These problems may be viewed as a result of establishing treatments without any consideration regarding the root cause of the cancer. Otto Warburg suggested that particular changes in the energy metabolism of cells, which are associated with a shortage of oxygen, are the root cause of cancer. Cancer cells have unique metabolic characteristics, and thus we believe that it is important to treat cancer as a metabolic disease. More specifically, not only is it important to suppress cancer cell metabolism, but it is also important to improve the chronic inflammation that is associated with the development and progression of cancer, and to support the functions of immune cells. This type of view of cancer treatment coincides with the principles of Chinese medicine, which has a history of 4000 years, such as “fuzheng quxie” and “zhibing qiuben”, which can assist in the establishment of cancer treatments for patients. In this article, we discuss cancer treatments from the view of cancer as a metabolic disease and their association with Chinese medicine, and introduce some clinical cases along with a review of the literature.

Therapeutic Potential, Challenges and Future Perspective of Cancer Stem Cells in Translational Oncology: A Critical Review.

Stem cell research is a rapidly developing field that offers effective treatment for a variety of malignant and non-malignant diseases. Stem cell is a regenerative medicine associated with the replacement, repair, and restoration of injured tissue. Stem cell research is a promising field having maximum therapeutic potential. Cancer stem cells (CSCs) are the cells within the tumor that posses capacity of selfrenewal and have a root cause for the failure of traditional therapies leading to re-occurrence of cancer. CSCs have been identified in blood, breast, brain, and colon cancer. Traditional therapies target only fast growing tumor mass, but not slow-dividing cancer stem cells. It has been shown that embryonic pathways such as Wnt, Hedgehog and Notch, control self-renewal capacity and involved in cancer stem cell maintenance. Targeting of these pathways may be effective in eradicating cancer stem cells and preventing chemotherapy and radiotherapy resistance. Targeting CSCs has become one of the most effective approaches to improve the cancer survival by eradicating the main root cause of cancer. The present review will address, in brief, the importance of cancer stem cells in targeting cancer as better and effective treatment along with a concluding outlook on the scope and challenges in the implication of cancer stem cells in translational oncology.

Abstract IA17: Non-invasive detection of somatic mutations in the management of CRC

Abstract Somatic mutations are exquisitely specific cancer biomarkers that are not merely associated with cancer, rather they are the root cause of cancer. The realization that this markers are present in bodily fluids of individuals with cancer and the development of digital methods for their detection ushered a new era in the management of cancer patients providing opportunities for the development of noninvasive methods for early detection, detection of minimal residual disease, monitoring of response to therapy, early detection of resistance and diagnosis. There are both technical and biological challenges for the development of noninvasive tests for the detection of somatic mutations. The number of circulating tumor DNA (ctDNA) molecules is very low compared to that of DNA molecules with wild-type sequence and requires very sensitive methods for their detection. To this end, we have developed a method called SafeSeqS that is able to reliably resolve mutations at 0.01% in background of wild-type DNA across multiple regions of interest. To determine the spectrum of cancers in which ctDNA measurements could prove clinically useful, we evaluated the detection of ctDNA in plasma (liquid biopsy) from patients with a large number of tumor types. ctDNA was detectable in the plasma of most patients with advanced tumor, but in less than 50% in patients with certain tumor types, like primary brain cancers. More than half of the patients with localized colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, had detectable ctDNA in their plasma. The sensitivity of detection of advanced colorectal cancer (CRC) was close to 100% and greater than 75% for localized cancers indicating that liquid biopsy could be utilized for a number of clinical applications. One such application is the detection of minimal residual disease after surgery or therapy with curative intent. Currently, there are not efficient ways to determine which patients are cured and which have residual disease that will result in recurrence. In a prospective cohort of 230 patients with resected stage II colon cancer, ctDNA detection after surgery provided direct evidence of residual disease and identified patients at very high risk of recurrence. Another application of liquid biopsy in CRC is monitoring resistance to therapies, like EGFR, providing an early indication that resistance ensues. The holy grail of non-invasive detection of cancer is early detection. Most tumors are incurable because they are detected at a late stage. Early detection of cancer, before symptoms appear, at a stage curable by surgery, holds great promise for decreasing the rate of deaths due to cancer. We will share our efforts on the development of tests for the early detection of cancer. Our overall vision is that non-invasive, somatic mutation based tests become routine in the clinical management of cancer patients. Citation Format: Nickolas Papadopoulos, Yuxuan Wang, Joshua Cohen, Ralph Hruban, Peter Gibbs, Jeanne Tie, Luis Diaz, Kenneth Kinzler, Bert Vogelstein. Non-invasive detection of somatic mutations in the management of CRC. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA17.

Curcumin in various cancers

Curcumin (diferuloylmethane), an active constituent of turmeric, is a well-described phytochemical, which has been used since ancient times for the treatment of various diseases. The dysregulation of cell signaling pathways by the gradual alteration of regulatory proteins is the root cause of cancers. Curcumin modulates regulatory proteins through various molecular mechanisms. Several research studies have provided in-depth analysis of multiple targets through which curcumin induces protective effects against cancers including gastrointestinal, genitourinary, gynecological, hematological, pulmonary, thymic, brain, breast, and bone. The molecular mechanisms of action of curcumin in treating different types of cancers remain under investigation. The multifaceted role of this dietary agent is mediated through its inhibition of several cell signaling pathways at multiple levels. Curcumin has the ability to inhibit carcinogenicity through the modulation of the cell cycle by binding directly and indirectly to molecular targets including transcription factors (NF-kB, STAT3, β-catenin, and AP-1), growth factors (EGF, PDGF, and VEGF), enzymes (COX-2, iNOS, and MMPs), kinases (cyclin D1, CDKs, Akt, PKC, and AMPK), inflammatory cytokines (TNF, MCP, IL-1, and IL-6), upregulation of proapoptotic (Bax, Bad, and Bak) and downregulation of antiapoptotic proteins (Bcl(2) and Bcl-xL). A variety of animal models and human studies have proven that curcumin is safe and well tolerated even at very high doses. This study elaborates the current understanding of the chemopreventive effects of curcumin through its multiple molecular pathways and highlights its therapeutic value in the treatment and prevention of a wide range of cancers.

Curcumin: A Challenge in Cancer Treatment

Oxidative damage initiates the inflammation and inflammation has been pointed out as the root cause of cancer and various other chronic diseases such as diabetes, hypertension, Alzheimer’s disease, etc. Epidemiological and clinical studies have suggested that cancer could be prevented or significantly reduced by appropriate treatment with anti-oxidant and anti-inflammatory drugs. Therefore, curcumin, a principal component of turmeric (curry spice) exhibiting strong anti-oxidant and anti-inflammatory activities, might be a potential candidate for the prevention and/or treatment of cancer and other chronic diseases. However, curcumin, in spite of its excellent safety profile, multitargeting effects and strong evidences on the molecular levels, could not achieve the desired therapeutic outcome in the past clinical trials, mainly due to its low solubility and poor bioavailability. Curcumin can be developed as a therapeutic drug through improvement in formulation properties or delivery systems, enabling its enhanced absorption and cellular uptake. This review mainly focuses on its anti-oxidant and anti-inflammatory potentials and recent developments in dosage form and delivery systems, opening the possibilities of therapeutic application of curcumin in the prevention and/or treatment of cancer.DOI: http://dx.doi.org/10.3126/jnpa.v26i1.6631 JNPA. XXVI(1) 2012 19-47

Characterization of a novel mouse model for human B-cell lymphomas (127.31)

Abstract The risk of developing lymphoma is markedly increased after solid organ transplantation. Up to 20% of people who receive a solid organ transplant develop a lymphoma. Calcineurin (CN) A beta knockout (Cnab-/-) mice do not reject allogeneic tumors suggesting an immunosuppressive state, is also a unique model for reverse immunosurveillance. Currently, there is no mouse model for low grade lymphomas based on immune dysregulation. Since we observed a spontaneous activation of T cells, and B-cell lymphomas in CNAβ deficient mice, we hypothesize that CN is involved in T-cell regulation, the lack of regulation causes smoldering inflammation which in turn activates B cells and results in lymphomagenesis. The lymphomas in Cnab-/- mice are positive for B cell surface marker (CD21) but negative for T cell (TCRβ) markers and they are clonal in origin and exhibit malignant (destroying the normal architecture of adjoining area) phenotype. In addition, we do see spontaneous activation of T cells in Cnab-/- mice early in life and continue to accumulate, and B cells later when they are old with mild inflammatory lesions in the gut and liver in Helicobacter-free (clean) colony. Since inflammation is considered to be one of the hallmarks of cancer and also the root cause of cancer, this is a novel mouse model for understanding a slow growing, difficult to cure form of lymphomas.

Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment.

Oxidative damage and inflammation have been pointed out in preclinical studies as the root cause of cancer and other chronic diseases such as diabetes, hypertension, Alzheimer’s disease, etc. Epidemiological and clinical studies have suggested that cancer could be prevented or significantly reduced by treatment with anti-oxidant and anti-inflammatory drugs, therefore, curcumin, a principal component of turmeric (a curry spice) showing strong anti-oxidant and anti-inflammatory activities, might be a potential candidate for the prevention and/or treatment of cancer and other chronic diseases. However, curcumin, a highly pleiotropic molecule with an excellent safety profile targeting multiple diseases with strong evidence on the molecular level, could not achieve its optimum therapeutic outcome in past clinical trials, largely due to its low solubility and poor bioavailability. Curcumin can be developed as a therapeutic drug through improvement in formulation properties or delivery systems, enabling its enhanced absorption and cellular uptake. This review mainly focuses on the anti-inflammatory potential of curcumin and recent developments in dosage form and nanoparticulate delivery systems with the possibilities of therapeutic application of curcumin for the prevention and/or treatment of cancer.

Stem cells: the intestinal stem cell as a paradigm.

Stem cell research provides a foundation for therapeutic advancement in oncology, clinical genetics and a diverse array of degenerative disorders. For example, the elucidation of pathways governing proliferative regulation and differentiation within cellular systems will result in medical strategies aimed at the root cause of cancer. At present the characterization of reliable stem cell markers is the immediate aim in this particular field. Over the past 30 years investigators have determined many of the physical and functional properties of stem cells through careful and imaginative experimentation. Intestinal stem cells reside at the crypt base and give rise to all cell types found within the crypt. They readily undergo altruistic apoptosis in response to toxic stimuli although their progeny are hardier and will regain stem cell function to repopulate the tissue compartment, giving rise to the concept of a proliferative hierarchy. Contention exists when deciding whether the full complement of cells within a crypt is derived from either a single or multiple stems. Evidence has also arisen to challenge the long held view that colorectal tumours arise from a single mutated stem cell, as early adenomas from a human XO/XY mosaic contained distinct clones. Mechanisms governing the stem cell cycle and subsequent proliferative activity largely remain obscure. The adenomatous polyposis coli gene product has, however, been shown to promote the degradation of beta-catenin, an enhancer of cell proliferation, thereby downregulating this activity in healthy individuals.