Series C: e-Books on Cancer & Oncology
Series C Content Consultant: Larry H. Bernstein, MD, FCAP
VOLUME TWO
Cancer Therapies:
Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery
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List of Contributors
Author, Curator and Editor:
Preface, Volume Introduction, Introductions and Summary of all Chapters, 1.1, 1.2, 1.2.2, 1.2.3, 1.2.4, 1.2.5, 1.2.6, 1.2.7, 1,2,8, 2.1, 2.1.2, 2.1.3, 2.1.4, 2.1.5, 2.1.6, 2.1.7, 2.2, 2.2.1, 2.2.2, 2.2.3, 2.2.4, 2.2.5, 2.2.6, 2.2.7, 2.2.8, 2.2.9, 2.2.10, 2.3.1, 2.3.3, 2.3.7, 2.3.8, 2.3.9, 2.3.10, 2.4.1, 2.4.2, 2.4.3, 2.4.4, 2.4.5, 2.4.6, 2.4.7, 2.4.8, 2.4.10, 3.0, 3.1 – 3.10, 4.1.1, 4.3.2, 4.3.3, 4.4, 4.4.1, 4.4.2, 4.5, 5.1, 6.2, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 7.1, 7.3, 7.5, 7.6, 7.7, 8.1, 8.2, 8.3, 9.1.2.5, 9.3.1.1, 9.5.1.2, 9.5.1.3, 10.1, 10.2, 10.3, 11.2, 11.4, 11.5, 11.6, 11.7, 11.8, 12.1, 12.3, 12.4, 13.1, 14.2.6, 14.6, 15.1, 15.2, 15.3, 15.5, 15.7.1 – 15.7.11, 16.4, 16.5, 16.7, 17.1, 17.2.1, 17.2.2, 17.2.3, 17.3.2.3, 17.3.2.4, 17.7, 17.8, 18.6, 19.1, 19.4, 19.5, Epilogue
Author, Curator and Editor:
Chapter Introductions and Summaries, 6.1.1, 6.1.1.2, 6.1.1.3, 6.1.1.4, 6.1.5, 6.1.6, 6.1.6.1, 6.1.6.2, 6.1.7, 6.3, 6.3.7, 6.3.8, 9.1.2.3, 9.5.1.1, 12.5, 16.8, 17.3.1, 17.3.2.1, 17.3.2.2, 17.3.2.5, 17.4, 17.6, 18.1, 18.2, 18.3, 18.4.1, 18.4.2, 19.4.3, 18.5, 20.1
Guest Authors and Curators:
4.2, 4.3.1
1.3.1, 1.3.3. 2.3.2, 2.2.4, 2.3.5, 3.11, 5.2, 6.1.2, 6.1.3, 6.1.4, 9.1.2.7, 12.2, 14.1, 14.1.1, 14.1.2, 14.2, 14.2.1, 14.2.2, 14.2.3, 14.2.4, 14.2.5, 14.3, 14.3.1, 14.3.2, 14.3.3, 14.3.4, 14.3.5, 14.3.6, 14.4.1, 14.4.3, 14.5.1, 14.5.2, 14.6.1, 14.6.2, 14.6.3, 14.6.4, 14.6.5, 14.6.6, 14.7, 14.7.1, 14.7.2
2.3.6, 2.4.9, 3.12, 7.2, 7.4, 7.8, 7.9, 11.3, 16.1, 16.2, 16.3, 17.5, 20.2.2
10.4, 14.4.2
15.4
15.6, 20.2.1
1.3.2, 8.4, 9.1.2.1, 9.1.2.2, 9.1.2.4, 9.1.2.6, 9.3.1.2, 11.1, 16.6, 19.1, 19.2, 19.3, 19.6, 19.7.1, 19.7.2, 19.8, 20.2.3, 20.2.4, 20.2.5, 20.2.6, 20.3.1, 20.3.2, 20.3.3, 20.3.4, 20.3.5
Abbreviated eTOCs
PREFACE by Larry H. Bernstein, MD, FCAP
Introduction to Cancer Therapies by Larry H. Bernstein, MD, FCAP
Part One: Cancer Genomic and Metabolic Targeted Pharmacotherapy
Chapter 1: Looking Into the Depths of the Cancer Metabolome
1.1 New methods for Study of Cellular Replication, Growth, and Regulation
1.2 Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases
1.2.1 DNA double strand breaks
1.2.2 RNAi – On Transcription and Metabolic Control
1.2.4 The Metabolic View of Epigenetic Expression
1.2.5 How Cancer Cells “Grab” Neighbors and “Reel them in”
1.2.6 Colorectal cancer stemness and ERK
1.3 Oncology in Childhood
1.3.1 Neuroblastoma: A review
1.3.2 The Genetic Origin of Childhood Acute Lymphoblastic Leukemia (ALL)
1.3.3 Acute Lymphoblastic Leukemia and Bone Marrow Transplantation
Summary
Chapter 2: Finding Dysregulation in the Cancer Cell
Introduction
2.1 Warburg Effect Revisited
2.1.2 Refined Warburg hypothesis
2.1.3 Warburg Effect and Mitochondrial Regulation
2.1.5 Mitochondrial Isocitrate Dehydrogenase (IDH) and variants
2.1.6 Mitochondrial pyridine nucleotides and Electron Transport Chain
2.1.7 Autophagy
2.2 New insights on the Warburg Effect
2.2.1 Therapeutic Implications for Targeted Therapy from the Resurgence of Warburg ‘Hypothesis’
2.2.2 Role of Nanobiotechnology in Developing Personalized Medicine for Cancer
2.2.4 Personalized Medicine is not yet here
2.2.5 Biomarkers for personalized oncology: recent advances and future challenges
2.2.6 Personalized oncology: recent advances and future challenges
2.2.7 Pharmacogenomic biomarkers for personalized cancer treatment
2.2.8 Limits to forecasting in personalized medicine: An overview
2.2.9 The genome editing toolbox: a spectrum of approaches for targeted modification
2.2.10 The Path to Personalized Medicine
2.3 Molecular Pathology of Cancer Progression
2.3.1 Halsted Model of Cancer Progression
2.3.2 The Molecular Pathology of Breast Cancer Progression
2.3.3 Metastatic Diseases
2.3.4 CD47: Target Therapy for Cancer
2.3.5 Colon Cancer
2.3.6 Renal (Kidney) Cancer: Connections in Metabolism at Krebs cycle and Histone Modulation
2.3.7 Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy
2.3.8 Lymph Node Metastases
2.3.9 Reactive Oxygen species in prostate cancer?
2.3.10 Glioma, Glioblastoma and Neurooncology
2.4 Hematological Cancer Progression
2.4.1 Hematologic Malignancies
2.4.2 Hematological Cancer Classification
2.4.3 Hematological Malignancy Diagnostics
2.4.4 Treatment of Acute Leukemias
2.4.5 Treatment for Chronic Leukemias
2.4.6 Treatment of Lymphomas
2.4.7 Treatments for Lymphomas and Leukemias
2.4.8 Update on Chronic Myeloid Leukemia
2.4.9 Pancreatic Cancer at the Crossroads of Metabolism
2.4.10 Better Cancer Medication
Summary
Chapter 3: Personalized Medicine in Cancer
Introduction
3.0 Personalized Medicine in Cancer: The Voice of Larry H. Bernstein, MD, FCAP
3.1 The path to personalized medicine
3.2 Role of Nanobiotechnology in Developing Personalized Medicine for Cancer
3.3 The HER-2 Receptor and Breast Cancer: Ten Years of Targeted
Anti–HER-2 Therapy and Personalized Medicine
3.4 Personalized Medicine is not yet here
3.5 Biomarkers for personalized oncology: recent advances and future challenges.
3.5.1 ZNF154 hypermethylation signature
3.6 Personalized oncology: recent advances and future challenges.
3.7 Pharmacogenomic biomarkers for personalized cancer treatment.
3.8 Limits to forecasting in personalized medicine: An overview
3.9 The genome editing toolbox: a spectrum of approaches for targeted modification
3.10 The Path to Personalized Medicine
3.11 Personalized Medicine and Colon Cancer
3.12 Personalized Medicine – The California Initiative
Part Two: Interventional Oncology
Chapter 4: Surgery
Introduction
4.1 Role of the Nervous System in Cancer Metastasis – NIH Study
4.1.1 Pain in Metastasis
4.2 Imaging Technology in Cancer Surgery
4.3 Metastatic Diseases – Examples of Surgical Procedures in Treatment of Cancer
4.3.1 Ablation Techniques in Interventional Oncology
4.3.2 Non-hematological Cancers
4.3.3 Examples of Surgical Procedures
4.4.1 Nanoscale photodynamic therapy
4.4.2 Alkalinizing to block tumor metastasis
4.5 Palliative care
Summary
Chapter 5: Radiation Therapy
Introduction
5.1 External beam radiotherapy (EBRT) & Brachytherapy
5.2 Photoacoustic Tomography
Chapter 6: Chemotherapy
Introduction by Dr. Stephen J. Williams, PhD
6.1 Cytotoxic Drugs
6.1.1 Why Does Cytotoxic Chemotherapy Still Remain a Mainstay in Many Chemotherapy Regimens
6.1.2 Thymosin alpha1 and melanoma
6.1.3 Paclitaxel: Pharmacokinetic (PK), Pharmacodynamic (PD) and Pharmacogenpmics (PG)
6.1.4 Paclitaxel vs Abraxane (albumin-bound paclitaxel)
6.1.5 War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert
6.1.6 Drug Resistance to Cytotoxic Therapies – Current Review
6.1.7 New Topoisomerase Inhibitors in Clinical Trials
6.2 Hematological Malignancies
6.3 Supportive Therapies
6.3.1 Bisphosphonates and Bone Metastasis
6.3.2 Blood transfusions
6.3.3 Erythropoietin
6.3.4 G-CSF (granulocyte-colony stimulating factor)
6.3.5 Plasma exchange (plasmapheresis)
6.3.6 Platelet transfusions
6.3.7 Steroids, Inflammation and CAR-T Therapy
6.3.8 Opioids, pain and Palliative Care
Part Three: Immunotherapy, Biologics Drugs Options & Targeted Therapies for the Immune System of the Cancer Patient
Introduction by Dr. Larry H Bernstein, MD, FCAP
Chapter 7: Viral and Vaccine Based Immunotherapy
7.1 Bacillus Calmette–Guérin (BCG) for superficial bladder cancer
7.2 Findings on Bacillus Calmette–Guérin (BCG) for Superficial Bladder Cancer
7.3 Papilloma viruses for cervical cancer
7.4 Observations on Human Papilloma Virus and Cancer
7.5 HCV NS5A Inhibitor from Theravance, Inc. to treat hepatitis C virus infection
7.6 GERD and Esophageal Adenocarcinoma
7.7 Helicobacter Pylorum
7.8 Viruses and Cancer: A Walk on the Memory Lane
7.9 In the name of Translation: Is it a far fetch? Friend or Foe? From a Food Born Pathogen Bacteria to become a friendly Vaccine
Chapter 8: Allogeneic Hematopoietic Stem Cell Transplantation and Graft versus Host
8.1 Hematopoiesis
8.2 Allogeneic Stem Cell Transplantation
8.3 Monitoring AML with “cell specific” blood test
8.4 Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology
Chapter 9: Latest Development in Immunotherapy in Cancer
9.1 Checkpoint Inhibitors
9.1.2 Articles on ‘PD-L1’
9.1.2.2 Immuno-Oncology Combination Therapy: Implications For Major Pharma
9.1.2.3 PD1 Inhibitor atezolizumab may show promise in bladder cancer in patients with high PDL1 expression
9.1.2.5 Novel biomarkers for targeting cancer immunotherapy
9.1.2.7 Pancreatic Cancer: Genetics, Genomics and Immunotherapy
9.2 Co-Stimulatory Agents
9.3 Immuno-modulators
9.3.1 Articles on CTLA4
9.3.1.1 Cancer Immunotherapy
9.3.1.2 Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma
9.4 Anti-Cancer – Four Drug Classes of Immune-Oncology Molecules in Development, including CAR-T
9.5 Fifth generation CAR (Chimeric Antigen Receptor T- cell) Signaling
9.5.1 Articles on ‘CAR-T’
9.5.1.1 Leaders in the CAR-T Field Are Proceeding With Cautious Hope
9.5.1.2 CAR-T therapy in leukemia
9.5.1.3 Rosa’s to like
Chapter 10: Aptamers and Small Peptide Inhibitors
10.1 Vaccines, Small Peptides, aptamers and Immunotherapy [9]
10.2 Angiogenesis Inhibitors
10.3 MDM2 inhibitor for the treatment of cancers
10.4 The Development of siRNA-Based Therapies for Cancer
Chapter 11: Additional Developments
11.1 Pfizer bets $1 billion on BioAtla Conditionally Active Biologics | BioAcceleration™ for Protein Therapeutics
11.2 Gene expression and adaptive immune resistance mechanisms in lymphoma
11.3 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology
11.4 Novel Oncologic Approach by Drug Trapping
11.5 Biomarkers of Cancer
11.6 Cancer Causing Enzyme Activity
11.7 Junk DNA and Breast Cancer
11.8 Aptamers and Scaffolds
Part Four: Hormonal Therapies
Chapter 12: Selective Hormone Therapy
12.1 Hormone Therapy
12.2 Role of progesterone in breast cancer progression
12.3 Hormone and Different Ovarian Cancers
12.4 Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group Ovarian Cancer
12.5 Are CXCR4 Antagonists Making a Comeback in Cancer Chemotherapy?
Part Five: Alternative Therapies
Chapter 13: Complementary and Alternative Therapies
13.1 Complementary and Alternative Therapies
Part Six: NanoTechnology, Nanoparticles and Drug Delivery
Chapter 14: Nanoparticles and Drug Delivery
14.1 Introduction to nanotechnology in Drug Delivery
14.1.1 Building a Drug-Delivery System (DDS): choice of polymers and drugs
14.1.2 Factors affecting the PK of the nanocarrier
14.2 Detection and Imaging
14.2.1 Single-Molecule Detection by Philip Tinnefeld
14.2.2 Mesothelin: An early detection biomarker for cancer (By Jack Andraka)
14.2.3 Nanotechnology and MRI imaging
14.2.4 Nanotechnology: Detecting and Treating metastatic cancer in the lymph node
14.2.5 Diagnosing lung cancer in exhaled breath using gold nanoparticles
14.2.6 Advanced Nanospectroscopy
14.3 Cancer Therapy
14.3.1 Nanotech Therapy for Breast Cancer
14.3.2 Ovarian Cancer and fluorescence-guided surgery: A report
14.3.3 Lung Cancer (NSCLC), drug administration and nanotechnology
14.3.4 Prostate Cancer and Nanotecnology
14.3.5 Nanotechnology Tackles Brain Cancer
14.3.6 Acute Lymphoblastic Leukemia (ALL) and Nanotechnology
14.4. Targeting DNA/RNA
14.4.1 DNA Nanotechnology
14.4.2 The Development of siRNA-Based Therapies for Cancer
14.4.3 Nanotechnology, personalized medicine and DNA sequencing
14.5 Transdermal Drug Delivery (DSS)
14.5.1 Introduction to Transdermal Drug Delivery (TDD) system and nanotechnology
14.5.2 Transdermal drug delivery (TDD) system and nanotechnology: Part II
14.6 Nanotechnology therapy for non-cancerous diseases
14.6.1 Introduction to Nanotechnology and Alzheimer disease
14.6.2 Nanotechnology and Heart Disease
14.6.3 Introduction to Tissue Engineering; Nanotechnology applications
14.6.4 Nanotechnology and Ocular Drug Delivery: Part I
14.6.5 Bone regeneration and nanotechnology
14.6.6 Nanotechnology and HIV/AIDS treatment
14.7 Hazards of Nanotechnology
14.7.1 Immunoreactivity of Nanoparticles
14.7.2 Nanotechnology and Health issues
Part Seven: Transitional Stages of Cancer
Chapter 15: In-situ Malignancy to Cancer
Introduction
15.1 Immunopathogenesis Advances in Diabetes and Lymphomas
15.2 Single Cell Shines Light on Cell Malignant Transformation
15.3 Nanosensors for Protein Recognition, and gene-proteome interaction
15.4 Scientists discover how cancer cells escape blood vessels
15.5 Deciphering the Epigenome
15.6 Swansea Uni uses artificial intelligence to detect cancer
15.7 Growth Factors, Suppressors and Receptors in Tumorigenesis
15.7.1 Quantum dots
15.7.2 Liposomal encapsulated drug
15.7.3 Protein-binding, Protein-Protein interactions & Therapeutic Implications
15.7.4 EpCAM
15.7.5 Upregulating Tumor Suppressor Pathways
15.7.6 Manipulating Signaling Pathways
15.7.7 Pathway Specific Targeting in Anticancer Therapies
15.7.8 Sirtuins
15.7.9 Hypoxia Inducible Factor 1 (HIF-1)
15.7.10 Wnt/β-catenin Signaling
15.7.11 Targeting the Wnt Pathway
Summary
Chapter 16: Reflections on the Promise of Monoclonal Antibody Therapy
Introduction
16.1 Personalized Medicine – The California Initiative
16.2 Monoclonal Antibody Therapy: What is in the name or clear description?
16.3 Monoclonal Antibody Therapy and Market
16.4 Trastuzumab (Herceptin) for breast cancer
16.5 Rituximab for a variety of B-cell malignancies
16.6 Metastatic Melanoma: Immunotherapy Drug Combination, Ipilimumab plus Nivolumab – Shrinks Tumor Size In 58% Skin Cancer Patients
16.7 Monoclonal antibody treatment of Multiple Myeloma: Elotuzumab
16.8 Fresolimumab
Part Eight: Research & Future Directions for Cancer Therapy and Prevention
Chapter 17: The Future of Oncology
17.1 Novel Approaches to Cancer Therapy
17.2 Personalized Medicine: New Diagnostics and Innovation in Pharmacokinetics
17.2.1 Novel biomarkers for targeting cancer immunotherapy
17.2.2 Nanotechnology: aptamers for specific & better delivery systems of existing drugs
17.2.3 Non-hematologic Cancer Stem Cells
17.3 Cancer Prevention
17.3.1 Early Diagnosis
17.3.2 Novel Diagnostics Methods
17.4 Rational Design of Allosteric Inhibitors and Activators Using the Population-Shift Model: In Vitro Validation and Application to an Artificial Biosensor
17.5 The Relation between Coagulation and Cancer affects Supportive Treatments
17.6 Tumor Associated Macrophages: The Double-Edged Sword Resolved?
17.7 Cancer and Nutrition
17.8 Environment and Cancer
Summary
Chapter 18: New Cancer Drugs in Clinical Trials
18.1 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer
18.2 Development of Chemoresistance to Targeted Therapies: Alterations of Cell Signaling & the Kinome
18.3 Novel Mechanisms of Resistance to Novel Agents
18.4 Toxic Responses Recorded for New Drugs in Clinical Trials
18.4.1 Liver Toxicity halts Clinical Trial of IAP Antagonist for Advanced Solid Tumors
18.4.2 Good and Bad News Reported for Ovarian Cancer Therapy
18.4.3 Novel Mechanisms of Toxicity Emerge
18.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee
18.6 Innovation In Cancer Biopharmaceutical Intelligence
Chapter 19: Relations between Cancer and Cardiovascular Diseases
19.1 Cancer, Respiration and the Peril of the Heart in Cancer Patients
19.2 Reuben Shaw, Ph.D., a geneticist and researcher at the Salk
Institute: Metabolism Influences Cancer
19.3 Heart Tumors: Etiology and Classification
19.4 Amyloidosis with Cardiomyopathy
19.5 Stabilizers that prevent Transthyretin-mediated Cardiomyocyte Amyloidotic Toxicity
19.6 Cancer Symptom Science: On the Mechanisms underlying the Expression of Cancer-related Symptoms
19.7 Therapies
19.7.2 Radiation and Chemotherapy Therapy: The Pharmacological Risk for Developing Cardiovascular Disease
19.8 3rd Annual Canadian Cardiac Oncology Network Conference, June 20 –21, 2013, Ottawa Convention Centre
Chapter 20: Cancer Research @Technion, Israel Institute of Technology
20.1 Recent Breakthroughs in Cancer Research at the Technion, Israel Institute of Technology, 2015
20.2 @Technion: Directions in Cancer Research
20.2.1 Medical Breakthrough: Israeli Researcher Predicts Where Cancer Will Spread
20.2.2 Pancreatic Cancer at the Crossroads of Metabolism
20.2.5 Immunity and Host Defense – A Bibliography of Research @Technion
20.2.6 Host – Tumor Interactions during Cancer Therapy – Dr. Yuval Shaked’s Lab @Technion
20.3 @Technion Deals, Partnerships, and Collaborations
20.3.3 Biomarkers of Cancer detected by BreathAnalyzer – An Collaborative effort of three Universities
20.3.4 Technion established the most advanced Center for Structural Biology in Israel
Epilogue
By Dr. Larry H. Bernstein, MD, FCAP
Preface
This volume on cancer and cancer therapeutics is somewhat a follow-up of the first, but it expands on the expansive research into the molecular studies of the basis of the group of diseases affecting many organs morphogenetically having specific roles and having specific time frames in their development. The classes of tumors have been divided into those that are benign and those that are malignant. Those that are benign are limited growths, but many have a transitional period between benign and malignant. Those that are malignant have features of nuclear changes, changes in the nuclear/cytoplasmic ratio, and may have some disruption of the architecture in the case of premalignant epithelium. Biologically the cells differentiate from primitive mesenchymal cells into three basic cell types – epithelial, mesenchymal (fibroblasts), and neuromuscular. Consequently, the endocrine organs of the body are solid epithelial cells with a supporting mesenchymal stroma. They function in biosynthesis, and therefore, have a requirement for NADPH for their function. The lining of hollow organs is epithelial, beneath which there is a mesenchymal layer, and beneath that is a muscularis. In all cases there is a vasculature lined by endothelial cells, with or without a muscular layer. The heart is a muscular organ with a unique neurological support, and the brain and spinal cord are neurological organs. Then there is the immune system and the hematological system that evolved in concert, with the evolution of an antibody mediated and a cell mediated immune system which is, humoral on the one hand, and thymus-derived, on the other hand. In addition, there is a lymphatic drainage system separate from the blood circulation. This is a not so simple or complete description of the anatomical and embryological features of the eukaryote and mammalian organism.
It is from this foundation that we have come to recognize the concept of malignant transformation prior to the molecular and biochemistry subcellular revolution that has occurred in the 20th century. Each organ has a different natural history of physiological function, and deviation from normal cellular behavior. The deviation may be preceded by years of chronic disease, and it may appear associated with virus, radiation, or environmental exposures, any or none of which can be ascertained. There may also be a family history, and a finding of a genomic signature, as with breast cancer and Her-2 Neu. The latter has become important for identifying “epidemiological risk” in a relationship to a population, but not necessarily a predictor of an individual’s risk, which poses a problem for counseling.
Introduction to Cancer Therapies
Part One
Cancer Genomic and Metabolic Targeted Pharmacotherapy
Larry H. Bernstein, MD, FCAP
Chapter 1
Looking Into the Depths of the Cancer Metabolome
Introduction
Cancer Cell Metabolism- There Is No ROS for the Weary
Chi V. Dang, Commentary on Ros et al., p. 328 (1).
Cancer Discov; 2(4); 304–7
http://dx.doi.org:/10.1158/2159-8290.CD-12-0069
Using a high-throughput short-hairpin RNA library screen targeting 222 metabolic nodes, Ros and colleagues identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), a glycolytic enzyme that shunts glucose into the pentose phosphate pathway for NADPH production, as a critical node for the survival of prostate cancer cells. Blocking PFKFB4 induces reactive oxygen species and cancer cell death, suggesting that PFKFB4 could be therapeutically targeted.
Cancer cells are on the go, adsorbing lipids and picking up nutrients for deregulated self-replication, which frequently culminates in the death of the host. In this issue of Cancer Discovery, Ros and colleagues (1) document the dependence of prostate cancer cells on 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), a glycolytic enzyme that plays an important role in attenuating reactive oxygen species (ROS) for the weary cancer cell to survive and in lipid synthesis for the cancer cell to replicate. Normal mammalian cells, such as cells of the gut or bone marrow, can replicate at significant rates for tissue homeostasis. Tissue stem cells or immune cells stimulated by growth factors or cytokines undergo a signal transduction and transcriptional program that permits both cell mass accumulation through macromolecular synthesis (e.g., lipid, protein, and nucleic acid synthesis) and acquisition of a commensurate bioenergetic supply. Nutrient-depleted, lowered energy conditions trigger AMP-activated protein kinase, which diminishes cellular ATP consumption and stimulates self-eating or autophagy to recycle cellular components as energy. In nutrient-replete conditions, glucose modulates transcription through its conversion to intracellular hexosephosphate and hexosamine, whereas glutamine import is required for activation of mTORC1 to stimulate cell growth (2, 3). Growth factor-receptor signaling further bolsters the cell growth program by activating mTORC2 and AKT, which can directly stimulate glycolysis, and early response genes such as MYC (Fig. 1A). The MYC gene produces a pleiotropic transcription factor that stimulates ribosome biogenesis, nucleotide synthesis, DNA replication, and the import of both glucose and glutamine to support the bioenergetic needs of a growing cell (4).
Figure 1 (not shown).
A, diagram depicts –
- Receptor signaling and nutrient import.
- Receptor signaling, through phosphoinositide 3-kinase (PI3K), stimulates mTORC2 and AKT as well as the MYC oncogene, which stimulates ribosome biogenesis and biomass accumulation for cell proliferation.
- Glucose and glutamine import stimulated by MYC induces mTORC1 and a collateral pathway of activating protein synthesis and ribosome biogenesis.
- Glutamine is shown converted to glutamate and then to α-ketoglutarate for further mitochondrial oxidation.
- Glucose is converted to lactate or to acetyl-CoA, which is further oxidized in the mitochondrion. Glucose is also shown shunted to the PPP to produce NADPH and ribose-5-phophate.
- B, glycolytic conversion of glucose to pyruvate and its conversion to ribose-5-phosphate via the pentose phosphate pathway.
- Glucose is transported into the cell and phosphorylated to glucose-6-phosphate by hexokinases, and then to fructose-6-phosphate by glucose phosphate isomerase.
- Fructose-6phosphate is phosphorylated by PFK1, which is positively allosterically regulated by fructose-2, 6-phosphate (F2, 6P), to fructose-1,6-phosphate and subsequently metabolized to pyruvate for further oxidation in the mitochondrion, a rich source of ROS.
- The levels of F2,6P are regulated by the PFK2 family members, PFKFB4 and TIGAR (a target of p53) that dephosphorylates F2,6P and PFKFB3 that generates F2,6P from fructose-2phosphate.
- Increased PFKFB4 or TIGAR lowers F2,6P and hence decreases PFK1 activity, shunting glucose-6-phosphate into the pentose phosphate pathway for production of ribose-5-phosphate and NADPH.
- NADPH reduces glutathione and thereby inhibits ROS.
Intriguingly, the necessity of PFKFB4 for cell survival extends beyond prostate cancer because other cancer cell lines are also sensitive to knockdown of PFKFB4 expression. Why PFKFB4 levels are elevated in prostate and other cancer cell lines is not known. Diminished PFKFB4 expression, however, does not seem to dramatically affect growth of the normal human prostate epithelial cell line RWPE1. Until there are further studies, it seems premature to suggest that PFKFB4 is not essential for normal cell proliferation in light of a significant overlap in the metabolic profiles of normal T cells and that of lymphoma. MYC induces glucose and glutamine metabolism in normal T-cell mitogenesis and proliferation of neoplastic lymphocytes, suggesting a significant overlap between normal and neoplastic cell metabolism. The difference, however, is that deregulated oncogene expression renders tumor cells addicted to nutrients.
All 3 prostate cancer cell lines studied by Ros and colleagues are highly glycolytic. It is notable, however, that RWPE1 is also glycolytic and does not display the truncated TCA cycle of normal prostate. Ros and colleagues also report the lack of significant dependence of these prostate cancer cell lines on glutamine, which contrasts with some previous published studies. It is notable that glutamine appears to be a significant substrate for the TCA cycle, particularly under hypoxia. In fact, glutamine can contribute to a significant fraction of lipids through its conversion to α-ketoglutarate and subsequent reductive carboxylation to isocitrate, which is then converted to citrate for lipid synthesis via ATP citrate lyase. Furthermore, under limiting glucose levels in the hypoxic tumor microenvironment, glutamine fills in the TCA cycle as well as supports the synthesis of glutathione. Notwithstanding these nuances, the article by Ros and colleagues and earlier studies from the laboratories of Cheng and Vousden, and Clem and colleagues underscore the importance of the PFK2 family of enzymes in tumor metabolism, which might be exploitable for cancer therapy.
- Ros S, Santos CR, Moco S, Baenke F, Kelly G, Howell M, et al. Functional metabolic screen identifies 6-phosphofructo-2-kinase/ fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival. Cancer Discov 2012; 2:328–43.
- Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2010; 12:21–35.
- Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 2011; 10:671–84.
- Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011;11:325–37.
The chapters that follow will elaborate on this concept, which is of great import to go beyond the initial conceptions of Otto Warburg in 1931.
1.1 New methods for Study of Cellular Replication, Growth, and Regulation
Larry H. Bernstein, MD, FCAP
1.2 Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases
Larry H. Bernstein, MD, FCAP
1.2.1 DNA double strand breaks
- Richard L Frock, et al
Nature Biotechnology 33,179–186 (2015) http://dx.doi.org:/10.1038/nbt.3101
http://www.nature.com/nbt/journal/v33/n2/full/nbt.3101.html
1.2.2 RNAi – On Transcription and Metabolic Control
Larry H. Bernstein, MD, FCAP
Larry H. Bernstein, MD, FCAP
1.2.4 The Metabolic View of Epigenetic Expression
Larry H. Bernstein, MD, FCAP
1.2.5 How Cancer Cells “Grab” Neighbors and “Reel them in”
Larry H. Bernstein, MD, FCAP
1.2.6 Colorectal cancer stemness and ERK
Larry H. Bernstein, MD, FCAP
1.3 Oncology in Childhood
1.3.1 Neuroblastoma: A review
Tilda Barliya, PhD
1.3.2 The Genetic Origin of Childhood Acute Lymphoblastic Leukemia (ALL)
Aviva Lev-Ari, PhD, RN
1.3.3 Acute Lymphoblastic Leukemia and Bone Marrow Transplantation
Tilda Barliya, PhD
Summary
The first chapter has covered a range of topics related to the metabolism and proliferation of cancer cells, which have been viewed as self-perpetuating without apoptosis. There is important consideration of enzyme catalysis in cell metabolic pathways and a relationship of metabolic expression to the term “epigenetics”. The term epigenetics is in common use, but it is not informative, intending to indicate cellular expression that is not transcribed from the genome. However, in the multiorgan species, differences in expression occur among organs in relationship to adaptation to the external and internal extracellular milieau. It also included the work on both inhibiting and noncoding RNAs, and also the work of Jennifer Duoda on DNA genomic engineering. It concluded with the childhood acute leukemias, and bone marrow transplants.
Chapter 2
Finding Dysregulation in the Cancer Cell
Introduction
This chapter is very basic to the understanding of cancer. It begins with the Warburg effect that was a seminal discovery in the 1920s by the great biochemist of that century. The Warburg effect is a defining characteristic of cancer cells. The chapter does on to cover key metabolic pathways involved in the uniqueness of cancer cells, that have much similarity of one to another, more so than the organ of origin. This is, however, somewhat overstated because it is well recognized that endocrine cancers are considerably more indolent than squamous and adenocarcinomas of non endocrine tissue. NO Kaplan hypothesized that endocrine organs are distinguished by the predominance of the NADP, synthetic form of pyridine nucleotide, and that energy dependent tissues have a predominance of the NAD form. The discussion of autophagy is important in the previously mentioned balance between repair and cell death (apoptosis). This is an insight that comes in the late twentieth century. Isocitrate dehydrogenase isoenzyme becomes important for a tie in with the impaired respiration of the malignant cell. Cell matastasis is discussed, and there is an introduction to personalized medicine.
2.1 Warburg Effect Revisited
Larry H. Bernstein, MD, FCAP
2.1.2 Refined Warburg hypothesis
Larry H. Bernstein, MD, FCAP
2.1.3 Warburg Effect and Mitochondrial Regulation
Larry H. Bernstein, MD, FCAP
Larry H. Bernstein, MD, FCAP
2.1.5 Mitochondrial Isocitrate Dehydrogenase (IDH) and variants
Larry H. Bernstein, MD, FCAP
2.1.6 Mitochondrial pyridine nucleotides and Electron Transport Chain
Larry H. Bernstein, MD, FCAP
2.1.7 Autophagy
Larry H. Bernstein, MD, FCAP
2.2 New insights on the Warburg Effect
Larry H. Bernstein, MD, FCAP
2.2.1 Therapeutic Implications for Targeted Therapy from the Resurgence of Warburg ‘Hypothesis’
2.2.2 Role of Nanobiotechnology in Developing Personalized Medicine for Cancer
2.2.4 Personalized Medicine is not yet here
2.2.5 Biomarkers for personalized oncology: recent advances and future challenges
2.2.6 Personalized oncology: recent advances and future challenges
2.2.7 Pharmacogenomic biomarkers for personalized cancer treatment
2.2.8 Limits to forecasting in personalized medicine: An overview
2.2.9 The genome editing toolbox: a spectrum of approaches for targeted modification
2.2.10 The Path to Personalized Medicine
2.3 Molecular Pathology of Cancer Progression
2.3.1 Halsted Model of Cancer Progression
Larry H. Bernstein, MD, FCAP
2.3.2 The Molecular Pathology of Breast Cancer Progression
Tilda Barliya, PhD
2.3.3 Metastatic Diseases
Larry H. Bernstein, MD, FCAP
2.3.4 CD47: Target Therapy for Cancer
Tilda Barliya, PhD
2.3.5 Colon Cancer
Tilda Barliya, PhD
2.3.6 Renal (Kidney) Cancer: Connections in Metabolism at Krebs cycle and Histone Modulation
Demet Sag, Ph.D., CRA, GCP
2.3.7 Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy
Larry H. Bernstein, MD, FCAP
2.3.8 Lymph Node Metastases
Larry H. Bernstein, MD, FCAP
2.3.9 Reactive Oxygen species in prostate cancer?
Larry H. Bernstein, MD, FCAP
2.3.10 Glioma, Glioblastoma and Neurooncology
Larry H. Bernstein, MD, FCAP
2.4 Hematological Cancer Progression
2.4.1 Hematologic Malignancies , Table of Contents
Larry H. Bernstein, MD, FCAP
2.4.2 Hematological Cancer Classification
Larry H. Bernstein, MD, FCAP
2.4.3 Hematological Malignancy Diagnostics
Larry H. Bernstein, MD, FCAP
2.4.4 Treatment of Acute Leukemias
Larry H. Bernstein, MD, FCAP
2.4.5 Treatment for Chronic Leukemias
Larry H. Bernstein, MD, FCAP
2.4.6 Treatment of Lymphomas
Larry H. Bernstein, MD, FCAP
2.4.7 Treatments for Lymphomas and Leukemias
Larry H. Bernstein, MD, FCAP
2.4.8 Update on Chronic Myeloid Leukemia
Larry H Bernstein, MD, FCAP
2.4.9 Pancreatic Cancer at the Crossroads of Metabolism
Demet Sag, PhD, CRA, GCP
2.4.10 Better Cancer Medication
Larry H. Bernstein, MD, FCAP
Summary
The second chapter covers material that is essential for an understanding of cancer biology. Foremost is the observation of impaired respiration and the mitochondrial pathways involved. While cancer cells replicate, the metabolic dependence is on the anaerobic pathways, which yield 2 ATP vs 38 ATP by aerobic metabolism through the Krebs Cycle (tricarboxylic acid cycle). In addition, there is also an equilibrium, or dysequilibrium between autophagy and apoptosis. As to the life of the host, the growing malignancy robs the host of metabolic nutrients and creates an environment in which there is a metabolic acidosis from lactic acidemia. Related to this phenomenon, There is a background proinflammatory state, and with it there is gluconeogenesis involving lean body mass. This results in the conversion of amino acid to glucose for fuel. This is the basis for cancer cachexia. The study of mechanism of the metastatic behavior of cancer cells has also been presented. When cancers reach the metastatic stage, it becomes the highlight of a systemic disease, and this introduces a focus on chemotherapy. This chapter also has covered both hematologic and solid organ malignancies.
Chapter 3
Personalized Medicine in Cancer
Introduction
The importance of personalized medicine is highlighted by the realization that cancers may retain characteristics of their organ of origin, they also differ with their types. This is apparent from the different biological behaviors between endocrine and non-endocrine tumors. It also is observed that cancers of the same type are different in their their behavior, and also that cancers have characteristics that are defining for malignancy. These tumors invade to regional lymph nodes and to distant sites. The patients having the same cancer have differences in histological grade and in cancer STAGE. Even this knowledge does not predict outcomes or choice of treatments with great success. The key to guide therapy requires a correct knowledge of genomic, metabolic, and regulatory features which are the necessary benchmark for targeting therapy. Only with such a knowledge will it be possible to develop a personalized oncologic treatment.
3.0 Personalized Medicine in Cancer: The Voice of Larry H. Bernstein, MD, FCAP
Larry H Bernstein, MD, FCAP
These topics are covered by the following twelve articles:
3.1 The path to personalized medicine
3.2 Role of Nanobiotechnology in Developing Personalized Medicine for Cancer
3.3 The HER-2 Receptor and Breast Cancer: Ten Years of Targeted
Anti–HER-2 Therapy and Personalized Medicine
3.4 Personalized Medicine is not yet here
3.5 Biomarkers for personalized oncology: recent advances and future challenges.
3.5.1 ZNF154 hypermethylation signature
3.6 Personalized oncology: recent advances and future challenges.
3.7 Pharmacogenomic biomarkers for personalized cancer treatment.
3.8 Limits to forecasting in personalized medicine: An overview
3.9 The genome editing toolbox: a spectrum of approaches for targeted modification
3.10 The Path to Personalized Medicine
3.11 Personalized Medicine and Colon Cancer
Tilda Barliya, PhD
3.12 Personalized Medicine – The California Initiative
Demet Sag, PhD, CRA, GCP
Summary
The material just completed covers the common interest in personalized medicine. The genomic revolution has given hope to a growing expectation of the emergence of personalized medicine. The task is still a difficult journey. Personalized medicine will require that individualized treatments are given to each patient with a defined malignancy. One factor in the discussion that can’t be ignored is the heterogeneity of expression within cancer types. Another consideration is that in cancer progression, there are mitotic changes that complicate the treatment. This results in the need for accurately identifying both genotype and phenotype because expression of the tumor is essential, and it also means that expression introduces a time domain in the process.
Part Two
Interventional Oncology
Chapter 4
Surgery
Introduction
The treatment of “tumors” by surgical means goes back centuries. The introduction of anesthesia for the treatment of pain introduced huge possibilities for progress in surgery. In the Eighteenth Century, there wer few physicians who were scientifically educated, and they were mainly in European countries. The best education available was in great institutions that had a tie in with religious scholarship. In the New World, many physicians were also ministers. This changed with the elimination of schools for medical and premedical education that had no basis in science. It came in the Twentieth Century with the Flexner Report, and Johns Hopkins University became the outstanding medical institution. Johns Hopkins had two among the giants of medical education – Halsted and Osler. They were indeed, the fathers of modern surgery and medicine. This chapter reviews the advances in surgery of cancer in the 20th Century.
4.1 Role of the Nervous System in Cancer Metastasis
NIH Study
4.1.1 Pain in Metastasis
Larry H. Bernstein, MD, FCAP
4.2 Imaging Technology in Cancer Surgery
Dror Nir, PhD
4.3 Metastatic Diseases – Examples of Surgical Procedures in Treatment of Cancer
4.3.1 Ablation Techniques in Interventional Oncology
Dror Nir, PhD
4.3.2 Non-hematological Cancers
Larry H. Bernstein, MD, FCAP
4.3.3 Examples of Surgical Procedures
Larry H. Bernstein, MD, FCAP
Larry H. Bernstein, MD, FCAP
4.4.1 Nanoscale photodynamic therapy
Larry H. Bernstein, MD, FCAP
4.4.2 Alkalinizing to block tumor metastasis
Larry H. Bernstein, MD, FCAP
4.5 Palliative care
Larry H. Bernstein, MD., FCAP
Summary
Chapter 4 has covered the progress of surgery in the treatment of cancer. The progress of surgical procedures has been highly dependent on the progress in radiology and interventional radiology, and as much dependent on the advances made in anesthesia and pain control. The progress in anesthesia gave better access to local excision with reduction of pain, and also to better management of the patients vital signs during long and difficult procedures. The advances in radiology led to surgical removal with greater precision under advanced imaging techniques.
Chapter 5
Radiation Therapy
Introduction
We have seen how important radiology contributed to the development of surgery. The first Nobel Prize in Physics went to Roentgen for his discovery of the x-ray, which gave rise to methods in both medical and non-medical use. This chapter introduces topics of interest in radiation as therapy.
UPDATED on 5/17/2021
Happy 80th Birthday: Radioiodine (RAI) Theranostics: Collaboration between Physics and Medicine, the Utilization of Radionuclides to Diagnose and Treat: Radiation Dosimetry by Discoverer Dr. Saul Hertz, the early history of RAI in diagnosing and treating Thyroid diseases and Theranostics
Guest Author: Barbara Hertz
5.1 External beam radiotherapy (EBRT) & Brachytherapy
Larry H.Bernstein, MD, FCAP
A Successful Case of Treatment of Prostate Cancer
“A Cardiff University professor whose pioneering research helped change the way prostate cancer is treated has been recognized with a major scientific award” Prof Malcolm Mason was recognized for his research in combining radiotherapy and hormone therapy. He thanked 1,025 men, mostly from the UK and Canada, who took part in a trial over 10 years. It showed the combined treatment significantly improved survival rates. In recognition of his work, Prof Mason, the head of Cardiff University’s Institute of Cancer and Genetics at the School of Medicine, was presented with the William Farr Medal at a dinner in London on Thursday. He said: “Prostate cancer accounts for 10,000 male deaths in the UK each year and is the second most common cause of cancer death in men, after lung cancer. Still alive “The trial was conducted because it was unknown whether radiotherapy would help to extend the lives of men with prostate cancer and reduce their chances of dying from their cancer.” What the trial proved, however, was that by providing radiotherapy in addition to hormone therapy, 74% of the men who took part in the trial were still alive after seven years, compared with 66% who did not have radiotherapy. All the men who took part in the randomized controlled trial – known in the UK as PR07 – between 1995 and 2005 had had “locally advanced” prostate cancer diagnosed, which had grown outside the surface of the prostate but had not spread further. Half the group were treated with hormone therapy, a standard form of drug treatment, and the other half with a combination of the same hormone therapy and an additional course of radiotherapy. The researchers also found that those who received radiotherapy were about half as likely to die of their prostate cancer. Prof Mason is also director of the Wales Cancer Bank, based at Velindre Hospital in Cardiff. The centre, one of the foremost of its kind in the world, has revolutionized opportunities for cancer research, collecting blood and tissue samples from thousands in Wales whether suffering from cancer or with a potential cancer diagnosis. Of his award, the professor said: “It’s always pleasing to be recognized but in reality this award goes to all the men who took part in this trial, which has shown radiotherapy to be so worthwhile for patients with the type of prostate cancer we call ‘locally advanced’ . “This is only just the start – the next stage will be to ensure that the results of this trial are implemented into treatment recommendations as quickly as possible,” he added. Cardiff University vice-chancellor Prof Colin Riordan congratulated Prof Mason on his “richly deserved award”, instituted by the Worshipful Society of Apothecaries. “By answering the important question of whether prostate cancer patients would benefit from radiotherapy, Prof Mason has helped alter the way prostate cancer is treated, making sure that treatment decisions are based on the best possible evidence.”
SOURCE
Itzhaz Golan, PhD
5.2 Photoacoustic Tomography
Tilda Barliya, PhD
Summary
We have covered here only a brief introduction to the contribution of radiology to cancer therapy.
Chapter 6
Chemotherapy
Stephen J. Williams, PhD
Introduction
This chapter is concerned with the actions and side effects of chemotherapy. Chemotherapy has been a very significant advance in medicine giving rise to the medical specialty of Oncology. The first victory in Oncology might have been traced to treatment of childhood leukemia in Boston Children’s Hospital. It is clear that this typr of treatment would be first to develop in treatment of blood disorders, which are systemic by definition. The use of chemotherapeutics has become important in advanced solid tumors with local or distant metastasis. This gives rise to a treatment based on grade and stage. Grade defines the characterization of the tumor in situ. Stage defines the characterization in terms of local or distant metastasis. Metastasis is an advanced invasion beyond the limits of confinement of the tumor. Both radiation and chemotherapy become essential in the treatment plan.
6.1 Cytotoxic Drugs
Stephen J. Williams, PhD
6.1.1 Why Does Cytotoxic Chemotherapy Still Remain a Mainstay in Many Chemotherapy Regimens
Stephen J. Williams, PhD
6.1.1.2 New Generation of Platinated Compounds to Circumvent Resistance
Stephen J. Williams, PhD
6.1.1.3 New Topoisomerase Inhibitors: Agents From Nature
Stephen J. Williams, PhD
6.1.1.4 Are Cyclin D Inhibitors a Good Target?
Stephen J. Williams, PhD
6.1.2 Thymosin alpha1 and melanoma
Tilda Barliya, PhD
6.1.3 Paclitaxel: Pharmacokinetic (PK), Pharmacodynamic (PD) and Pharmacogenpmics (PG)
Tilda Barliya, PhD
6.1.4 Paclitaxel vs Abraxane (albumin-bound paclitaxel)
Tilda Barliya, PhD
6.1.5 War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert
Stephen J. Williams, PhD
6.1.6 Drug Resistance to Cytotoxic Therapies – Current Review
Stephen J. Williams, PhD
6.1.6.1 Can IntraTumoral Heterogeneity Be Thought of as a Mechanism of Resistance?
Stephen J. Williams, PhD
6.1.6.2 Cancer Stem Cells As A Resistance Mechanisms
Stephen J. Williams, PhD
6.1.7 New Topoisomerase Inhibitors in Clinical Trials
Stephen J. Williams, Ph.D.
6.2 Hematological Malignancies
Larry H. Bernstein, MD, FCAP
6.3 Supportive Therapies
Stephen J. Williams, PhD
6.3.1 Bisphosphonates and Bone Metastasis
Stephen J. Williams, PhD
6.3.2 Blood transfusions
Larry H. Bernstein, MD, FCAP
6.3.3 Erythropoietin
Larry H. Bernstein, MD, FCAP
6.3.4 G-CSF (granulocyte-colony stimulating factor)
Larry H. Bernstein, MD, FCAP
6.3.5 Plasma exchange (plasmapheresis)
Larry H. Bernstein, MD, FCAP
6.3.6 Platelet transfusions
Larry H. Bernstein, MD, FCAP
6.3.7 Steroids, Inflammation and CAR-T Therapy
Stephen J Williams, PhD
6.3.8 Opioids, pain and Palliative Care
Stephen J Williams, PhD
Summary
This chapter has covered major advances in the use of oncologic drugs and the side effects to consider. These drugs are often given concurrently with radiation therapy, and in many advanced diseases, there is multi-drug therapy. Chemotherapy is an emerging discipline. Therapy has to be adjusted in many cases because of multi-drug resistance. Just as in antibiotic treatment for infection, cancer treatment is confounded by drug resistance. As malignancy progresses, there is usually a concomitant resistance when the malignancy does not recede. In addition, there may be remission, only to see recurrence some time later.
Part Three
Immunotherapy, Biologics Drugs Options &
Targeted Therapies for the Immune System of the Cancer Patient
Introduction
Larry H Bernstein, MD, FCAP
This project has been the most intense search for answers in my career as a pathologist. It was perhaps made somewhat necessary after my retirement from a career in clinical pathology with a feeling of not having finished my life work, which began in my childhood reading of Paul De Kruif’s Microbe Hunters, and continued with my readings in collegiate course in scientific German. I began serious work on the crystallins of the eye lens and also on the ontogeny of the lactic dehydrogenase isoenzymes in the laboratory of Prof. Harry Maisel after my sophomore year in medical school, and when I graduated in 1968, I had chosen a career in pathology, but a career limited to service in anatomic pathology would not be a good fit. I was mentored in residency by a superb pathologist and biochemist who suggested after a year that I work in the laboratory of Nathan O. Kaplan, at University of California, San Diego, where I completed my training in biochemistry and enzymology, in particular, and also completed my residency in pathology under Averill Liebow. It was an intense experience. Unappreciated by me at the time, NO Kaplan never used the terminology for the pyridine nucleotide coenzymes – NAD and NADP – but stuck to the terms used by Otto Warburg, DPN and TPN. I was still not prepared for the half century old hypothesis by Warburg that cancer involves a dysmetabolism of the mitochondrion, and he had referred to the work 60 years earlier by Louis Pasteur to identify in the proliferation of cancer cells, a reliance on glycolysis (as in fermentation), even in the presence of oxygen. However, in my first academic appointment I continued studies of the mitochondrial and cytoplasmic malate dehydrogenases. I developed a simple assay to determine the ratio of the two activities based on the work done earlier on differences in their inhibition by a ternary complex formed between oxaloacetate and the NAD+ formed during the forward reaction with the reduced coenzyme. I also obtained fast growing and minimal deviation hepatocellular carcinoma tissue from my Chairman, Herschel Sidransky, and found interesting differences between cytoplasmic malate dehydrogenases from benign liver, minimal deviation and fast growing cancer that I could not continue long term.
The Warburg investigations have been re-explored in a new light in the 21st century. The scientific instrumentation and the computational tools available today have brought a greater depth to biological and medical sciences, which has given real promise to a reconstruction of pharmaceutical sciences. This is the case for infectious diseases, autoimmune disease, diabetes, genetic diseases, cardiovascular disease, endocrinology, and also cancer.
The difficulty with cancer has been the variety of presentations and courses of development for carcinogenesis by types of tissue, age, and sex, as well as differences within types. This has been made clear by the significant number of mutations that have been uncovered associated with cancers in humans and animal models. The first generations of cancer therapies were directed at DNA and replication, and they have carried toxicities to nonmalignant cells. However, we have unlocked an inner dimension of cells in which there are networks of interacting pathways that are involved in cellular regulation. We also have a much better grasp of the processes of cell replication, cellular remodeling, proliferation, and cell death, which ranges from some degree of autophagia involving mitochondria, the endoplasmic reticulum, and the lysosome, and cell death (apoptosis). The proteins, enzymes and pathways have been evolved for thousands of years, and are of primordial descent.
This chapter is concerned with the possibilities for pharmaceutical developments in cancer for the near future. It will cover the outlined subchapters. It is based on extensive searches for articles using a combination of sources. The basic theme of these presentations will be in more than one direction as follows:
- The encapsulation of a drug on conjugates so embedded that the action is locally directed to the site of the tissue disrupted.
- The targeting of specific pathways related to cancer oncogenes, or more specifically, having a key role in cell proliferation, cell adhesion, and metastatic potential.
- The effect of overexpression of identified pathways, and the effect of suppression of the same pathways, and the interaction between other key pathways that are upregulated or downregulated.
- The investigation of these mechanisms brings one to some conclusion about the amazing intricacy of how we age, and how we interact with a stressful environment.
This is what makes it difficult to design a treatment that is the so thought of “magic bullet”, and it necessitates more than one course of treatment, and combination treatments will probably not go away. However, there may still be many opportunities for treatments that are optimum for the patient and the condition. In addition, there is another dimension that was not so possible even a decade ago.
The clear knowledge of how these pathways are related to the particular cancer, and the ability to measure the substrates and small molecules involved has introduced a better way to follow the effectiveness of treatment, and at an early stage.
The reader will find that not all of the treatments are necessarily by use of a monoclonal antibody. All of the reactions do rely on an intermolecular reaction like a lock-and-key that binds with a critical small molecule that is critically engaged in a regulatory process. Whether it is sufficient is a matter to be discovered. We are now familiar with a library of terms, such as, conformational change, linkers, promoters, inhibitors, upregulation, downregulation, baggage-carriers, heteromer, dimer, trimer, etc. These all are players in this process.
Chapter 7
Viral and Vaccine Based Immunotherapy
Introduction
Larry H. Bernstein, MD, FCAP
7.1 Bacillus Calmette–Guérin (BCG) for superficial bladder cancer
Larry H. Bernstein, MD, FCAP
7.2 Findings on Bacillus Calmette–Guérin (BCG) for Superficial Bladder Cancer
Demet Sag, PhD, CRA, GCP
7.3 Papilloma viruses for cervical cancer
Larry H. Bernstein, MD, FCAP
7.4 Observations on Human Papilloma Virus and Cancer
Demet Sag, PhD, CRA, GCP
7.5 HCV NS5A Inhibitor from Theravance, Inc. to treat hepatitis C virus infection
Larry H. Bernstein, MD, FCAP
7.6 GERD and Esophageal Adenocarcinoma
Larry H. Bernstein, MD, FCAP
7.7 Helicobacter Pylorum
Larry H. Bernstein, MD, FCAP
7.8 Viruses and Cancer: A Walk on the Memory Lane
Demet Sag, PhD, CRA, GCP
7.9 In the name of Translation: Is it a far fetch? Friend or Foe? From a Food Born Pathogen Bacteria to become a friendly Vaccine
Demet Sag, PhD, CRA, GCP
Summary – Pending
Chapter 8
Allogeneic Hematopoietic Stem Cell Transplantation and Graft versus Host
Introduction – Pending
8.1 Hematopoiesis
Larry H. Bernstein, MD, FCAP
8.2 Allogeneic Stem Cell Transplantation
Larry H. Bernstein, MD, FCAP
8.3 Monitoring AML with “cell specific” blood test
Larry H. Bernstein, MD, FCAP
8.4 Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology
Aviva Lev-Ari, PhD, RN
Summary – Pending
Chapter 9
Latest Development in Immunotherapy in Cancer
Introduction
Stephen J. Williams, PhD – Pending
Four Drug Classes of Immune-Oncology Molecules in Development, including CAR-T
9.1 Checkpoint Inhibitors
- PD-1
- PD-L1 (Programmed Death (PD))
- LAG-3
- TIM-3
9.1.2 Articles on ‘PD-L1’
Aviva Lev-Ari, PhD, RN
9.1.2.2 Immuno-Oncology Combination Therapy: Implications For Major Pharma
Aviva Lev-Ari, PhD, RN
9.1.2.3 PD1 Inhibitor atezolizumab may show promise in bladder cancer in patients with high PDL1 expression
Stephen J Williams
Aviva Lev-Ari, PhD, RN
9.1.2.5 Novel biomarkers for targeting cancer immunotherapy
Larry H. Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN
9.1.2.7 Pancreatic Cancer: Genetics, Genomics and Immunotherapy
Tilda Barliya, PhD
9.2 Co-Stimulatory Agents
- CD137/41BB
- OX40
- CD27
- GITR
- CD40
9.3 Immuno-modulators
- CTLA4 (cytotoxic T Lymphocyte Associated protein-4)
- KIR
- IDO IL-2
- IL-21
- CSF1R
- Vaccines
SOURCE: Page 66 in
http://jpmorgan.metameetings.com/confbook/healthcare16/stash/misc/IO%20Combos.pdf
9.3.1 Articles on CTLA4
9.3.1.1 Cancer Immunotherapy
Larry H. Bernstein, MD, FCAP
9.3.1.2 Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma
Aviva Lev-Ari, PhD, RN
9.4 Anti-Cancer – Four Drug Classes of Immune-Oncology Molecules in Development, including CAR-T
- Phase of Development,
- Drug Name
- Pharma Name
- Target Disease Indication
Curator: Stephen J. Williams, PhD
Phase inDevelop-ment |
Checkpoint InhibitorsDrug/Pharma |
Co-Stimulatory AgentsDrug/Pharma |
ImmunomodulatorsDrug/Pharma |
Fifth Generation CAR SignalingPharma/PartnersDrug(Target/disease indication) |
Pre-Clinical |
REGN2810/RegeneronPD-1/AgenusAnti-Lag3/Tesaro, AnaptyBioIMP701/Prima BioMedLAG3/Agenus, IncyteLag3/MerckAnti-TIM3/BristolAnti-TIM3/Tesaro, AnaptyBioAnti-TIM3/Agenus |
OX40/AmgenGITR/BristolGITR/PfizerFPA154/Five PrimeAnti-GITR/TG TherapeuticsAnti-GITR/Incyte |
CTLA4/AgenusIDO1/Pfizer,iTEOSF001287/Bristol,FlexusIMA942/RocheVIBR/Pfizer |
Kite Pharma/AmgenMultiple targets/ hematologic & solid tumorsBellicum PharmaBPX-401 (CD19/leukemia)BPX-601 (PSCA/prostate)BPX-701 (PRAME/melanomaCellectis/PfizerCornel/Ohio StateUCART123 (CD123/AML)UCARTCS1 (CD38/multiple myeloma)UCART 38 (CD38 /multiple myeloma)UCART 22 ( CD22/ALL)Juno Therapeutics/CellgeneMUC116 (IL12/ovarian)ROR1 (ROR1/B-ALL)Univ. of Penna/NovartisCAR-T hPSMA (PSMA/prostate) |
Phase I |
BMS986016/Bristol |
Urelumab/ BristolMyersMEDI-0562/ AstraZenecaRG7888/RocheOX40/AgonoxOX40/GSKMK-4166/MerckSEA-CD40/Seattle GeneticsCD40/Roche |
Anti-CEA Il2v/RocheFPA008/Bristol, Five PrimeLY3022855/LillyAMG820/AmgenARRY382/Array, Celgene |
Ziopharm/Intrexon/ MD AndersonCD19 (CD19/B-ALL)Kite Pharma/AmgenKTE-C19 (ZUMA-3/Adult ALL)KTE-C19 (ZUMA-4/pediatric ALL)EGFRvII (EGFR/glioblastoma)Bluebird Bio/Cellgene/Baylorbb2121 (BCMA/B-ALL)Juno Therapeutics/CellgeneJCAR017 (CD19/leukemias)JCAR014 (CD19/NHLymphoma) |
Phase I/II |
MEDI0680/AstraZenec |
PF-05082566/PfizerVarilumab/Celldex, Bristol-Myers |
NKG2A/Innate,AstraZen.dCellVax/BioMatrixAPN301/Apeiron, MerckKGA |
Juno Therapeutics/CellgeneJCAR015 (CD19/ALL)JTCR016 (WT-1/AML,CML) |
Phase II |
Pidlizumab/MedivationAvelumab/Pfizer, MerckKGa |
Lirilumab/BMY/InnateEpacadostat/Incyte, MerckGDC-0919/NewLinkGenetics, RocheTG4010/Transgene S.A.Ontak/Esai, Lilly, TevaDenenicokin/Bristol, NovoNordiskPLX3397/Plexikon, MerckMCS110/NovartisJNJ40346527/JNJT-Vec/AmgenEmactuzumab/Roche |
Univ. of Penna/NovartisCTL019 (CD19/leukemia)Kite Pharma/AmgenKTE-C19 (ZUMA-1/leukemia)KTE-C19 (ZUMA-2/mantle cell leukemia) |
|
Phase III |
Duvalumab/AstraZencaAtezolizumab/Roche |
Tremelimumab/AstraZeneca |
||
Approved |
Opdivo/Bristol-MyersKeytruda/Merck |
Yervoy/Bristol-Myers |
9.5 Fifth generation CAR (Chimeric Antigen Receptor T- cell) Signaling
CAR-T: T cells are genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CARs).
9.5.1 Articles on ‘CAR-T’
9.5.1.1 Leaders in the CAR-T Field Are Proceeding With Cautious Hope
Stephen J. Williams, Ph.D.
9.5.1.2 CAR-T therapy in leukemia
Larry H. Bernstein, MD, FCAP
9.5.1.3 Rosa’s to like
Larry H. Bernstein, MD, FCAP
Immune-Oncology Summary
Stephen J Williams, PhD – Pending
Chapter 10
Aptamers and Small Peptide Inhibitors
10.1 Vaccines, Small Peptides, aptamers and Immunotherapy [9]
Larry H. Bernstein, MD, FCAP
10.2 Angiogenesis Inhibitors
Larry H Bernstein, MD, FCAP
10.3 MDM2 inhibitor for the treatment of cancers
Larry H. Bernstein, MD, FCAP
10.4 The Development of siRNA-Based Therapies for Cancer
Ziv Raviv, PhD
Chapter 11
Additional Developments
11.1 Pfizer bets $1 billion on BioAtla Conditionally Active Biologics | BioAcceleration™ for Protein Therapeutics
Aviva Lev-Ari, PhD, RN
11.2 Gene expression and adaptive immune resistance mechanisms in lymphoma
Larry H. Bernstein, MD, FCAP
11.3 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology
Demet Sag, PhD, CRA, GCP
11.4 Novel Oncologic Approach by Drug Trapping
Larry H. Bernstein, MD, FCAP
11.5 Biomarkers of Cancer
Larry H. Bernstein, MD, FCAP
11.6 Cancer Causing Enzyme Activity
Larry H. Bernstein, MD, FCAP
11.7 Junk DNA and Breast Cancer
Larry H. Bernstein, MD, FCAP
11.8 Aptamers and Scaffolds
Larry H. Bernstein, MD, FCAP
Part Four
Hormonal Therapies
Chapter 12
Selective Hormone Therapy
12.1 Hormone Therapy
Larry H. Bernstein, MD, FCAP
12.2 Role of progesterone in breast cancer progression
Tilda Barliya, PhD
12.3 Hormone and Different Ovarian Cancers
Larry H. Bernstein, MD, FCAP
12.4 Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group Ovarian Cancer
Larry H. Bernstein, MD, FCAP
12.5 Are CXCR4 Antagonists Making a Comeback in Cancer Chemotherapy?
Stephen J. Williams, PhD
Part Five
Alternative Therapies
Chapter 13
Complementary and Alternative Therapies
13.1 Complementary and Alternative Therapies
Larry H. Bernstein, MD, FCAP
The Voice of Larry H Bernstein, MD, FCAP
This chapter proceeded essential information about the pharmaco-oncologic treatment of cancer not previously discussed. It included discussions of complementary and alternative medicines. These treatments have not undergone clinical trials, and in several examples this should be considered. Most important is that these offer very low toxicity. Also important is the use of hormone therapy, which was established after the discovery of hormones in cancer progression. Also known is the simple fact of hormone resistance. The treatment with anti-angiogenesis agents has not proved efficacious in a experience despite the great promise expected. Allogeneic stem cell transplantation and graft-versus host reaction are also covered.
Part Six
NanoTechnology, Nanoparticles and Drug Delivery
Tilda Barliya, PhD
Chapter 14
Nanoparticles and Drug Delivery
14.1 Introduction to nanotechnology in Drug Delivery
Tilda Barliya, PhD
14.1.1 Building a Drug-Delivery System (DDS): choice of polymers and drugs
Tilda Barliya, PhD
14.1.2 Factors affecting the PK of the nanocarrier
Tilda Barliya, PhD
14.2 Detection and Imaging
Tilda Barliya, PhD
14.2.1 Single-Molecule Detection by Philip Tinnefeld
Tilda Barliya, PhD
14.2.2 Mesothelin: An early detection biomarker for cancer (By Jack Andraka)
Tilda Barliya, PhD
14.2.3 Nanotechnology and MRI imaging
Tilda Barliya, PhD
14.2.4 Nanotechnology: Detecting and Treating metastatic cancer in the lymph node
Tilda Barliya, PhD
14.2.5 Diagnosing lung cancer in exhaled breath using gold nanoparticles
Tilda Barliya, PhD
14.2.6 Advanced Nanospectroscopy
Larry H. Bernstein, MD, FCAP
14.3 Cancer Therapy
Tilda Barliya, PhD
14.3.1 Nanotech Therapy for Breast Cancer
Tilda Barliya, PhD
14.3.2 Ovarian Cancer and fluorescence-guided surgery: A report
Tilda Barliya, PhD
14.3.3 Lung Cancer (NSCLC), drug administration and nanotechnology
Tilda Barliya, PhD
14.3.4 Prostate Cancer and Nanotecnology
Tilda Barliya, PhD
14.3.5 Nanotechnology Tackles Brain Cancer
Tilda Barliya, PhD
14.3.6 Acute Lymphoblastic Leukemia (ALL) and Nanotechnology
Tilda Barliya, PhD
14.4. Targeting DNA/RNA
Tilda Barliya, PhD
14.4.1 DNA Nanotechnology
Tilda Barliya PhD
14.4.2 The Development of siRNA-Based Therapies for Cancer
Ziv Raviv, PhD
14.4.3 Nanotechnology, personalized medicine and DNA sequencing
Tilda Barliya, PhD
14.5 Transdermal Drug Delivery (DSS)
Tilda Barliya, PhD
14.5.1 Introduction to Transdermal Drug Delivery (TDD) system and nanotechnology
Tilda Barliya, PhD
14.5.2 Transdermal drug delivery (TDD) system and nanotechnology: Part II
Tilda Barliya, PhD
14.6 Nanotechnology therapy for non-cancerous diseases
Larry H. Bernstein, MD, FCAP
14.6.1 Introduction to Nanotechnology and Alzheimer disease
Tilda Barliya, PhD
14.6.2 Nanotechnology and Heart Disease
Tilda Barliya, PhD
14.6.3 Introduction to Tissue Engineering; Nanotechnology applications
Tilda Barliya, PhD
14.6.4 Nanotechnology and Ocular Drug Delivery: Part I
Tilda Barliya, PhD
14.6.5 Bone regeneration and nanotechnology
Tilda Barliya, PhD
14.6.6 Nanotechnology and HIV/AIDS treatment
Tilda Barliya, PhD
14.7 Hazards of Nanotechnology
Tilda Barliya, PhD
14.7.1 Immunoreactivity of Nanoparticles
Tilda Barliya, PhD
14.7.2 Nanotechnology and Health issues
Tilda Barliya, PhD
Part Seven
Transitional Stages of Cancer
Chapter 15
In-situ Malignancy to Cancer
Introduction
Immunotherapy has advanced over the last half century. The use of antibodies has historical been for identification in diagnostics. Immunology was initially only concerned with B-cells and antibodies, and owes much to Robert Good, MD, a pioneer in pediatric immunology. The production of antibodies initially was polyclonal, which resulted in a mixture of antibodies. This changed with the introduction of monoclonal antibodies. However, this was no simple matter. It complicated the production of diagnostic antibodies because two manufactured monoclonal antibodies might recognize a different ligand for binding site. This chapter, however, is focused on the use of antibodies for immunotherapy. The application of monoclonal antibodies is clearly the best choice, provided the target binding site is the definitive site. In addition to the antibody, there has been the emerging technology for the delivery of the immunotherapy. That is a topic for discussion. The related chapter on nanotechnology and aptamers is a separate chapter.
15.1 Immunopathogenesis Advances in Diabetes and Lymphomas
Larry H. Bernstein, MD, FCAP
15.2 Single Cell Shines Light on Cell Malignant Transformation
Larry H. Bernstein, MD, FCAP
15.3 Nanosensors for Protein Recognition, and gene-proteome interaction
Larry H. Bernstein, MD, FCAP
15.4 Scientists discover how cancer cells escape blood vessels
Danut Dragoi, PhD
15.5 Deciphering the Epigenome
Larry H. Bernstein, MD, FCAP
15.6 Swansea Uni uses artificial intelligence to detect cancer
Evelina Cohn, PhD
15.7 Growth Factors, Suppressors and Receptors in Tumorigenesis
Larry H. Bernstein, MD, FCAP
15.7.1 Quantum dots
Larry H. Bernstein, MD, FCAP
15.7.2 Liposomal encapsulated drug
Larry H. Bernstein, MD, FCAP
15.7.3 Protein-binding, Protein-Protein interactions & Therapeutic Implications
Larry H. Bernstein, MD, FCAP
15.7.4 EpCAM
Larry H. Bernstein, MD, FCAP
15.7.5 Upregulating Tumor Suppressor Pathways
Larry H. Bernstein, MD, FCAP
15.7.6 Manipulating Signaling Pathways
Larry H. Bernstein, MD, FCAP
15.7.7 Pathway Specific Targeting in Anticancer Therapies
Larry H. Bernstein, MD, FCAP
15.7.8 Sirtuins
Larry H. Bernstein, MD, FCAP
15.7.9 Hypoxia Inducible Factor 1 (HIF-1)
Larry H. Bernstein, MD, FCAP
15.7.10 Wnt/β-catenin Signaling
Larry H. Bernstein, MD, FCAP
15.7.11 Targeting the Wnt Pathway
Larry H. Bernstein, MD, FCAP
Summary
I introduced these presentations with a message of high complexity and intricate networks that govern our cells. We have had a spectacular development in the research on genomics, but the picture was incomplete. There are repeated discoveries of new oncogenes that are related to cancer discoveries. In some cases they have had a large impact on diagnosis and relationship to an at risk population, most notably in breast cancer. Then there is the long history of PSA in prostate cancer. These are biomarkers, and biomarkers of another generation are coming into play. These biomarkers are the signaling molecules that are directly involved in the tumorigenesis progression.
While we know about the large number of genomes that can develop mutations over a lifetime, we cannot necessarily make a determination of cause and effect. In addition, the study of genomics is not necessarily related to phenotypic observables. The genome is the script, and it is not directly engaged in the dynamic processes of the living cell. We now have a host of molecular agents that interact with genetic chromatin, or interact with the cytoskeleton, which can have an impact in the immediate cell structure and function. There are small RNAs, large RNAs, and peptides and proteins. The cell is engaged with other cells by an intercellular matrix, by transport proteins, by pore structures that convey electrolytes, and the cell is sensitive to hydrostatic pressure and to temperature.
We also see that there are protein substrate, and protein-protein interactions that occur in close proximity and affect protein conformation. These many reactions occur in milliseconds to maybe a hundredth of a millisecond. This is the architecture needed to survive in a stressful environment, which might arise intracellularly as well as extracellulary.
This chapter has gone into much detail about the relationship of signaling cascades and key regulatory targets involved in cell stemness, cell proliferation, cell aggregation, and cell metastasis. The reactions discussed don’t bring into the discussion of a dimension of the metabolic process that also needs consideration. Some reactions have been unknown until the development of mass spectroscopy. If there is a reaction, we have to consider either a cationic cofactor, or a nucleotide catalyst. Briton Chance pioneered the study of in vivo cell monitoring for changes in the ratio of NADH/NAD+. This is a dynamic viewing of cellular processes.
There are three articles in the Apr 15, 2015 issue of Genetic Engineering News (Genengnews.com) that are specifically related to this discussion.
- Vicki Glasser – Diverse Pathways to Drug Targets.
Protein paths through the gene-expression undergrowth have been well trodden, but RNA paths want wear too.
More than 90 percent of the genome that is transcribed into RNA is not translated into protein, and the growing numbers of naturally occurring microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) being identified and characterized, the important role that they have in normal biological processes and diseases is becoming ever more clear. An example to illustrate this point is the case of a Phase II clinical study of micravirsen, antisense oligonucleotide, in patients with hepatitis C (hep C), published in 2013 in the New England Journal of Medicine that describes its effectiveness as dependent on the miR-122 binding hepC for stability, and inhibition of miR-122 in HCV infected patients was associated with decreased levels of HCV that continued beyond the treatment period.
However, does this also apply to cancer. According to George Calin and coworkers at MD Anderson Cancer Center, Houston, Tx, regulatory RNAs – both miRNAs and other ncRNAs are being investigated to identify miRNAs of about 21-22 nucleotides length that can serve as reliable biomarkers for cancer diagnosis and to guide treatment. These miRNAs are stably expressed in tumor cells and the exosomes are present in body fluids, where they act like hormones and signaling molecules. The work was described in 2014 in CA: A Cancer Journal for Clinicians (“MicroRNAome genome: a treasure for cancer diagnosis and therapy”, and was also presented in Feb 2014 at the Molecular Med Tri Conference in San Francisco. Nevertheless, finding a miRNA target is difficult because an individual miRNA could have a role in regulating tens, hundreds, and even thousands of protein-coding genes. The message is to identify mRNAs that affect a single pathway of interest to help limit off-target effects. The solution depends on identifying which metabolic and/or signaling pathways are activated of inhibited.
- Lisa Heiden – Precision Tuning GPCR PathwaysG protein coupled receptors (GPCRs) are essential drug targets for therapeutic intervention due to their integral roles in a plathora of fundamental signal transduction pathways. But discovering, designing, and synthesizing GPCR-targeted compounds for modulating signaling has been difficult, mainly because the pathways are so complex. Consequently, of 800 proteins that have been classified as GPCRs only drugs have been developed against only 50.
- Kate Marusina – RNA Constructs: Thread Translational Needle
Noncoding RNA plays a major role in gene expression and gene regulation, and its malfunction often results in abnormal cellulat activity. This understanding led to the development of treatment strategies that use RNA both as therapeutics targets and treatment agents. This years’ Gordon Conference on Nanotechnology is dedicated to RNA nanotechnology research. Cancer pathways and miRNAs (that regulate the expression of more than 90 percent of the human genome) are linked, according to Carlo Croce at Ohio State University Institute of Genetics. miRNA is often the downstream target of an initial tumorigenic event. Dr. Croce’s team identified a cause of chronic lymphocytic leukemia (CLL) in a chromosomal region that is lost in 70 percent of CLL, which contains two miRNA genes, miRNA-15 and mi-RNA-16. They demonstrated that these are negative regulators of another gene in the cascade, BCL-2. In May 2014 AbbVie presented results from a Phase Ib clinical trial of ABT-199, a BCL-2 selective inhibitor. The response rate was 84% in patients with relapsed/refractory CLL. Furthermore, Peixuan Guo’s team at University of Kentucky Nanobiotechnology Center introduced the phi29 motor pRNA nanotechnology that is a hexameric pRNA nanoparticle with a ribozyme, a receptor-binding aptamer, a siRNA, an image reporter molecule, a bound drug site, and a component for endosome disruption. The key to success will be sustaining tumor suppression using the scaffold, targeting ligands and therapeutic modules that can be composed entirely of RNA. The prototype was achieved by packaging bacteriophage phi29 (pRNA) fragments designed to form multimeric RNA nanoparticles with defined size and structure.
Chapter 16
Reflections on the Promise of
Monoclonal Antibody Therapy
Introduction
This chapter has two not concordant issues. The first is the relationship to viruses and chronic inflammatory agents to the risk of developing cancer. It is not clear what the causal relationship is in some cases. The second is the emergence of monoclonal antibodies use in the treatment of cancers. In the first statement we have good knowledge of the relationship of hepatitis B and C to the long term risk of hepatoma, and of human papilloma virus to the risk of cervical cancer, and of a relationship of gastro-duodenal ulcer, and of gastric reflux to cancer risk. In the second statement we have far greater specificity for both diagnosis and for treatment in the development of monoclonal antibodies. There are limitations to the use of monoclonal antibodies. In diagnostics, a test for a disease marker may be directed at different sites on a protein identifier. In the case of treatment, the case may arise if there is a similar monoclonal antibody that is non-identical at the target site for two pharmaceutical drugs.
16.1 Personalized Medicine – The California Initiative
Demet Sag, PhD, CRA, GCP
16.2 Monoclonal Antibody Therapy: What is in the name or clear description?
Demet Sag, PhD, CRA, GCP
16.3 Monoclonal Antibody Therapy and Market
Demet Sag, PhD, CRA, GCP
16.4 Trastuzumab (Herceptin) for breast cancer
Larry H. Bernstein, MD, FCAP
16.5 Rituximab for a variety of B-cell malignancies
Larry H. Bernstein, MD, FCAP
16.6 Metastatic Melanoma: Immunotherapy Drug Combination, Ipilimumab plus Nivolumab – Shrinks Tumor Size In 58% Skin Cancer Patients
Aviva Lev-Ari, PhD, RN
16.7 Monoclonal antibody treatment of Multiple Myeloma: Elotuzumab
Larry H. Bernstein, MD, FCAP
16.8 Fresolimumab
Stephen J. Williams, Ph.D.
Summary
This chapter has covered in considerable depth the research into viruses and infection in the development of certain cancers. The mechanism is not known, except that there is a long term risk. In addition, we have reviewed some important types of cancer, the relationship to virus or inflammatory factor risk. Finally, we have explored the oncologic treatment of cancer using some very well established monoclonal onco-therapies.
Part Eight
Research & Future Directions for Cancer Therapy and Prevention
Chapter 17
The Future of Oncology
Introduction
The material that follows builds on what has come before. Surgery and radiation therapy have improved substantial in the last half century, but they have limits. Radiotherapy will expand with the use of radiopharceutical probes to target cancers, which puts this treatment alongside of pharmacotherapy. Pharmaceutical therapy has enormous potential for improvement by improving the selectivity of the agents used and by reducing the toxicity to proximate non-malignant tissue. This is not going to be an easy task. Treating a cancer is like hitting a moving target and the dimensions we have to work in have time and space limitations. Given the changing mileau of the malignant tissue based on metabolic, signaling, and translational dynamics, we will have to face adjustment of treatments during a treatment phase, and we have to be prepared for recurrence. The challenge is not only in the science. The cost of pharmacotherapy is rising faster than our current medical system can handle.
17.1 Novel Approaches to Cancer Therapy
Larry H. Bernstein, MD, FCAP
17.2 Personalized Medicine: New Diagnostics and Innovation in Pharmacokinetics
17.2.1 Novel biomarkers for targeting cancer immunotherapy
Larry H. Bernstein, MD, FCAP
17.2.2 Nanotechnology: aptamers for specific & better delivery systems of existing drugs
Larry H. Bernstein, MD, FCAP
17.2.3 Non-hematologic Cancer Stem Cells
Larry H. Bernstein, MD, FCAP
17.3 Cancer Prevention
17.3.1 Early Diagnosis
Stephen J. Williams, PhD
17.3.2 Novel Diagnostics Methods
Stephen J. Williams, PhD
17.3.2.2 New scheme to routinely test patients for inherited cancer genes
Stephen J. Williams, PhD
17.3.2.3 Cancer Biomarkers
Larry H. Bernstein, MD, FCAP
17.3.2.4 BRCA 1 and 2 and Early Detection of Cancer
Larry H. Bernstein, MD, FCAP
17.3.2.5 Personalized Medicine: Clinical Aspiration of Microarrays
Stephen J. Williams, PhD
17.4 Rational Design of Allosteric Inhibitors and Activators Using the Population-Shift Model: In Vitro Validation and Application to an Artificial Biosensor
Stephen J. Williams, PhD
17.5 The Relation between Coagulation and Cancer affects Supportive Treatments
Demet Sag, PhD, CRA, GCP
17.6 Tumor Associated Macrophages: The Double-Edged Sword Resolved?
Stephen J. Williams, PhD
17.7 Cancer and Nutrition
Larry H. Bernstein, MD, FCAP
17.8 Environment and Cancer
Larry H. Bernstein, MD, FCAP
Summary
The last chapter has considered some of the recent advances in pharmacotherapy for cancers based on good science. There has also been a presentation of some innovators as well as innovative methods for the leukemias, and for solid tumors. These treatments have involved better methods to arrest tumor growth and metastasis.
Chapter 18
New Cancer Drugs in Clinical Trials
Stephen J. Williams, PhD
Introduction – Pending
18.1 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer
Stephen J. Williams, PhD
18.2 Development of Chemoresistance to Targeted Therapies: Alterations of Cell Signaling & the Kinome
Stephen J. Williams, PhD
18.3 Novel Mechanisms of Resistance to Novel Agents
Stephen J. Williams, PhD
18.4 Toxic Responses Recorded for New Drugs in Clinical Trials
18.4.1 Liver Toxicity halts Clinical Trial of IAP Antagonist for Advanced Solid Tumors
Stephen J. Williams, PhD
18.4.2 Good and Bad News Reported for Ovarian Cancer Therapy
Stephen J. Williams, PhD
18.4.3 Novel Mechanisms of Toxicity Emerge
Stephen J. Williams, PhD
18.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee
Stephen J. Williams, PhD
18.6 Innovation In Cancer Biopharmaceutical Intelligence
Larry H. Bernstein, MD, FCAP
Summary – Pending
Chapter 19
Relations between Cancer and Cardiovascular Diseases
Aviva Lev-Ari, PhD, RN
19.1 Cancer, Respiration and the Peril of the Heart in Cancer Patients
Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN
19.2 Reuben Shaw, Ph.D., a geneticist and researcher at the Salk
Institute: Metabolism Influences Cancer
Aviva Lev-Ari, PhD, RN
19.3 Heart Tumors: Etiology and Classification
Aviva Lev-Ari, PhD, RN
19.4 Amyloidosis with Cardiomyopathy
Larry H Bernstein, MD, FACP
19.5 Stabilizers that prevent Transthyretin-mediated Cardiomyocyte Amyloidotic Toxicity
Larry H. Bernstein, MD, FCAP
19.6 Cancer Symptom Science: On the Mechanisms underlying the Expression of Cancer-related Symptoms
Aviva Lev-Ari, PhD, RN
19.7 Therapies
Aviva Lev-Ari, PhD, RN
19.7.2 Radiation and Chemotherapy Therapy: The Pharmacological Risk for Developing Cardiovascular Disease
Aviva Lev-Ari, PhD, RN
19.8 3rd Annual Canadian Cardiac Oncology Network Conference, June 20 –21, 2013, Ottawa Convention Centre
Aviva Lev-Ari, PhD, RN
Chapter 20
Cancer Research @Technion,
Israel Institute of Technology
Stephen J. Williams, PhD
Introduction – Pending
20.1 Recent Breakthroughs in Cancer Research at the Technion, Israel Institute of Technology, 2015
Stephen J. Williams, PhD
20.2 @Technion: Directions in Cancer Research
20.2.1 Medical Breakthrough: Israeli Researcher Predicts Where Cancer Will Spread
Evelina Cohn Budu, PhD
20.2.2 Pancreatic Cancer at the Crossroads of Metabolism
Demet Sag, PhD, CRA, GCP
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
20.2.5 Immunity and Host Defense – A Bibliography of Research @Technion
Aviva Lev-Ari, PhD, RN
20.2.6 Host – Tumor Interactions during Cancer Therapy – Dr. Yuval Shaked’s Lab @Technion
Aviva Lev-Ari, PhD, RN
20.3 @Technion Deals, Partnerships, and Collaborations
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
20.3.3 Biomarkers of Cancer detected by BreathAnalyzer – An Collaborative effort of three Universities
Aviva Lev-Ari, PhD, RN
20.3.4 Technion established the most advanced Center for Structural Biology in Israel
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Summary – Pending
Stephen J. Williams, PhD
Epilogue
Therapeutic Implications for Targeted Therapy from the Resurgence of Warburg ‘Hypothesis’
Larry H. Bernstein, MD, FCAP
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