Cancer

癌症 Cancer

• Understanding Cancer: Metastasis, Stages of Cancer, and More
  • Malignant Tumors Vs. Benign Tumors
  • Cancer Metastasis
  • What Causes Cancer?
  • Cancer Symptoms and Signs
  • Types of Cancer
  • 7 Common Cancers
  • How Stages of Cancer Are Determined
  • What Are The Stages of Cancer?
  • Diagnosing Cancer
  • What Are Treatment Options? Surgery, Radiation Therapy, Chemotherapy Procedure
• 生活中9種引發癌症最危險的因子
• 用手機就是在微波你的大腦？手機電磁波真的會致癌？, 致癌分級
• This Graphic Shows What Really Matters in Preventing Cancer
• 幫助身體修復，愈活愈健康！癌病專家教你遠離癌症
  • 養成良好的睡眠順序習慣
  • 提升副交感神經系統、降低交感神經系統的刺激

避開身邊致癌物

一半以上癌症可預防　避開身邊6種致癌物

食物

• 如何吃, 如何烹調, 吃什麼
• 吃蔬果可防癌化？係金A！
• 抗癌: 番茄紅素 綠色蔬菜 蔥蒜 素食 辛香料
• 致癌: 黃麴黴 aflatoxin, 苯並芘 Benzopyrene, 亞硝胺 Nitrosamine. 丙烯醯胺
• 抗癌不能瘦 補充營養品增肌肉
• 逆轉癌病　名醫：7種好食物，餓死癌細胞
• 大白菜/Chinese cabbage - 冬季護膚 防癌

植物油 vegetable oil

• Glycidol 縮水甘油
  • 巧克力、麵包恐藏致癌物「縮水甘油」，如何避免？ 棕櫚油被發現所含的縮水甘油較高.

低溫烹調

100℃低溫烹調　少吃到致癌物質

另類療法

名醫自己如何抗癌 48 招. 用經絡儀 來測量12經絡能量平衡與提升。

走路

做1件事降13種癌症風險

癌症指數

癌症指數怎麼看？正常值是多少？「指數高不等於罹癌」醫師教你如何解讀

Different stage of cancer

• TNM staging system, Cancer Staging.
• http://seer.cancer.gov/cgi-bin/glossary/glossary.pl
  • In situ cancer is early cancer that is present only in the layer of cells in which it began.
  • Localized cancer is cancer that is limited to the organ in which it began, without evidence of spread.
  • Regional cancer is cancer that has spread beyond the original (primary) site to nearby lymph nodes or organs and tissues.
  • Distant cancer is cancer that has spread from the primary site to distant organs or distant lymph nodes.
  • Unstaged cancer is cancer for which there is not enough information to indicate a stage.

Tumor types

Cancer Classification

Carcinoma

• Carcinomas are divided into two major subtypes:
  • adenocarcinoma, which develops in an organ or gland, and
  • squamous cell carcinoma, which originates in the squamous epithelium.
• What is carcinoma?
• Sarcoma vs. Carcinoma: Differences and Similarities.
  • Carcinomas are much more common, accounting for 85% to 90% of cancers. Sarcomas, in contrast, represent slightly less than 1% of cancer types. (The other types of cancer include leukemias, lymphomas, and myelomas, although some cancers may have characteristics of more than one type, for example, carcinosarcomas.)
  • Carcinomas arise out of epithelial cells that line the surface and organs of the body, whereas sarcomas arise from connective tissues such as bone, cartilage, fibrous tissue, blood vessels, and nerves.
  • Carcinomas tend to be more common in people over the age of 50, but can occur in young adults and children. Sarcomas may occur at any age, but are often diagnosed in children and young adults. Roughly 15% of cancers diagnosed in people less than 20 years of age are sarcomas.
• 上皮細胞間質化（Epithelial to mesenchymal transition/EMT）, 循環腫瘤細胞（Circulating tumor cells）, 遠端轉移
  • 感覺晚上精神特別好？癌細胞也是——趁你熟睡時偷偷進行的「癌症轉移機制」 大部分的上皮細胞癌（譬如說大部分的乳癌、卵巢癌等等）都喜歡聚在一起，當細胞被打散反而生長得比較差，甚至無法生長。但是當這些細胞準備要遠端轉移時，他們會由表皮細胞轉換成間質細胞，脫離原本的基質，進入血液循環。因此很多癌症只要有遠端器官轉移，就屬於三期癌症以上，無法進行局部治療（譬如手術切除），而必須要進行系統性治療，譬如像是化學治療、賀爾蒙治療、標靶治療、免疫療法等等。
  • 上皮-間質轉化 (Epithelial-Mesenchymal Transition, EMT) 是一種細胞生物學現象，是指上皮細胞轉化成為間質細胞的過程。在此過程中，上皮細胞失去其上皮細胞的特徵，如細胞極性和細胞-細胞黏附能力，同時獲得了間質細胞的特徵，如增加細胞運動性和抗凋亡能力。EMT 通常發生在胚胎發育、創傷修復和癌症轉移等生理和病理狀態中。
  • 在癌症中，EMT 可能促進腫瘤細胞的轉移和侵犯，增加其生存能力和抵抗治療的能力。EMT 還可能促進癌症幹細胞的形成，這些幹細胞被認為是癌症治療失敗和復發的主要原因之一。
  • EMT 的調節是一個復雜的過程，涉及到許多調節分子和信號通路。例如，轉錄因子 Snail、Slug、Twist 和 ZEB1 等都被證明可以抑制上皮細胞標誌物的表達，並啟動間質標誌物的表達。此外，細胞外基質成分、細胞腔內環境、細胞間通訊等因素也可能參與調節 EMT。
  • 抑制上皮細胞標誌物的表達是 EMT 過程中的一個重要步驟，它會使得癌細胞失去上皮細胞的特徵，增加細胞的運動性和侵犯性，促進癌細胞轉移。
  • EMT 過程中的轉錄因子(transcription factors) Snail、Slug、Twist 和 ZEB1 等被證明可以抑制 (repress) 上皮細胞 epithelial cell 標誌物 markers (CDH1) 的表達，啟動 (promote) 間質 mesenchymal 標誌物的表達，進而促進 EMT 的發生。這些轉錄因子在多種癌症中均被發現過度表達，並與癌症轉移和惡性程度有關。
  • 這些轉錄因子在多種癌症中都被發現過度表達，這可能是促進癌細胞轉移和侵犯的原因之一。例如，在乳腺癌、前列腺癌、膀胱癌、大腸癌等多種癌症中，Snail、Slug、Twist 和 ZEB1 的表達均被觀察到過度表達。

Sarcoma

• https://en.wikipedia.org/wiki/Sarcoma
• What is sarcoma?

Rare cancer

• About Rare Cancers from cancer.gov
• News
  • What to know about Merkel cell carcinoma/MCC, Jimmy Buffett’s rare cancer, Merkel-cell carcinoma

Tumor microenvironment/TME

當心腫瘤的左鄰右舍，談腫瘤微環境 張金堅. extracellular matrix/ECM, Stromal cells, tumor-associated macrophage/TAM,

Differentiated tumor (grade), stage

• NCI Dictionary of Cancer Terms.
  • In biology, describes the processes by which immature cells become mature cells with specific functions.
  • In cancer, this describes how much or how little tumor tissue looks like the normal tissue it came from. Well-differentiated cancer cells look more like normal cells and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells.
• What does differentiated mean? Most types of cancer are divided into three grades of differentiation – well differentiated, moderately differentiated, and poorly differentiated.
  • The grade is important because more differentiated cancers (well and moderately differentiated) tend to grow more slowly and spread less frequently than less differentiated cancers (poorly differentiated and undifferentiated).
  • Undifferentiated cells = cancer cells (look nothing like normal cells)
• The Histologic Grading of Cancer 1995
• Cancer Grade vs. Cancer Stage. Cancer cells that look and organize most like healthy cells and tissue are low grade tumors. Doctors describe these cancers as being well differentiated.
  • Grade 1: Tumor cells and tissue looks most like healthy cells and tissue. These are called well-differentiated tumors and are considered low grade.
  • Grade 4: These undifferentiated cancers have the most abnormal looking cells. These are the highest grade and typically grow and spread faster than lower grade tumors.
• Differentiation is a way of describing how similar cancer cells are to normal cells, and it is used to classify cancer into different types.
  • Differentiated cancer cells are those that resemble normal cells of the tissue from which they originated. These cells tend to grow and spread in a more organized way, and they are often considered to be less aggressive than undifferentiated cancer cells. Differentiated cancer cells tend to be less likely to invade surrounding tissue and to spread to other parts of the body. They are also more likely to respond well to traditional treatments such as chemotherapy and radiation.
  • Undifferentiated cancer cells, on the other hand, do not resemble normal cells of the tissue from which they originated. These cells tend to grow and spread in a more chaotic and disorganized way, and they are often considered to be more aggressive than differentiated cancer cells. They tend to be more likely to invade surrounding tissue and to spread to other parts of the body. They are also less likely to respond well to traditional treatments such as chemotherapy and radiation.
  • It's worth noting that cancer histological type can be a combination of both differentiated and undifferentiated cells, and also the differentiation of cancer cells can change over time, for example, a well-differentiated cancer may progress to an undifferentiated form over time.
  • Histological classification of cancer is important for diagnosis, prognosis, and treatment decisions. Understanding the histological type of a cancer can provide important information about the cancer's behavior and potential response to treatment.
• STAGING & GRADE for breast cancer
• How histological differentiation is measured?
  • Histological differentiation is usually measured by analyzing tissue samples obtained through a biopsy. The samples are then examined under a microscope by a pathologist, who can assess the degree of differentiation of the cancer cells.
  • The pathologist will look at the size, shape, and organization of the cells, as well as their nuclei, cytoplasm, and other cellular components. They will also assess the presence and intensity of certain markers, such as proteins or enzymes, which are characteristic of normal or cancer cells.
  • Different histological techniques are used to measure the level of differentiation of cancer cells, such as Hematoxylin and Eosin (H&E) staining, which is the most widely used for general histological examination. Some other techniques used to analyze cancer cell differentiation are immunohistochemistry, in situ hybridization, electron microscopy, and special stains like Periodic acid-Schiff (PAS) and Alcian blue.
  • The pathologist will then compare the appearance of the cancer cells to normal cells of the same tissue type, and based on this comparison, assign the cancer a grade of differentiation. The grade of differentiation is usually divided into well-differentiated, moderately differentiated, and poorly differentiated, with well-differentiated cancer cells resembling normal cells most closely, and poorly differentiated cancer cells looking the most abnormal.
  • It's worth noting that the assessment of histological differentiation can be subjective, and it may vary among pathologists. Therefore, it's important for the pathologist to have a good understanding of the normal anatomy and histology of the tissue, as well as the criteria for differentiating cancer cells from normal cells.
• In general, what are the proportions of differentiated and undifferentiated types in cancer patients?
  • The proportion of differentiated and undifferentiated cancer cells can vary depending on the type of cancer. In general, well-differentiated cancer cells tend to be less aggressive and have a better prognosis than poorly differentiated or undifferentiated cancer cells.
  • For example, in breast cancer, well-differentiated tumors, known as ductal carcinoma in situ (DCIS), are considered to have a relatively good prognosis and a low risk of metastasis, while poorly differentiated or undifferentiated tumors, known as triple-negative breast cancer, are considered to have a poorer prognosis and a higher risk of metastasis.
  • In lung cancer, well-differentiated tumors, known as adenocarcinomas, tend to have a better prognosis than undifferentiated tumors, such as squamous cell carcinomas or large cell carcinomas, which have a poorer prognosis.
  • In colon cancer, well-differentiated tumors, known as adenomas, are considered to be less aggressive than undifferentiated tumors, such as signet ring cell carcinomas which are considered to be more aggressive and have a poorer prognosis.
  • In general, it's worth noting that the proportion of differentiated and undifferentiated cells can vary depending on the type and stage of cancer, and that the proportion of undifferentiated cells is often associated with a poorer prognosis and a higher risk of recurrence and metastasis.

Metastasis 轉移

• 癌症轉移 走兩路線 血液 淋巴 台灣大腸癌地圖 這區死亡率最高？ 大腸癌6大症狀 綠拿鐵黃金比例護腸. 血液通常跑到 身體血流豐富的地方: 肝臟 肺臟 骨頭.
• What to Expect When Cancer Spreads to the Bones

Histology

• https://en.wikipedia.org/wiki/Histology 組織學/顯微解剖學
• Histology is the branch of biology concerned with the study of the microscopic structure of tissues. It involves examining thin slices of tissue under a microscope, often using stains to distinguish different biological structures.
• Histology, also known as microscopic anatomy, is the branch of biology that studies the microscopic structure of biological tissues. It's typically divided into several categories based on the type of tissue being studied. Here are some examples:
  • Epithelial Tissue: This tissue covers the body surface and lines its cavities. Subtypes include simple squamous, simple cuboidal, simple columnar, pseudostratified columnar, stratified squamous, stratified cuboidal, stratified columnar, and transitional epithelium¹.
  • Connective Tissue: This tissue supports, binds, or separates other tissues or organs. Subtypes include loose connective tissue, dense connective tissue, cartilage, bone, blood, and lymph¹.
  • Muscle Tissue: This tissue is responsible for producing force and motion. Subtypes include smooth muscle, skeletal muscle, and cardiac muscle¹.
  • Nervous Tissue: This tissue is the main component of the nervous system, which regulates and controls body functions. It includes the central nervous system and the peripheral nervous system¹.
  • In addition to these, there are specialized fields within histology:
    • Histopathology: This is the microscopic examination of biological tissues to observe the appearance of diseased cells and tissues in very fine detail¹.
    • Cytology: This is the study of cells, including their function, chemistry, and structure¹.
    • Paleohistology: This is the study of ancient, fossilized tissues¹.

Cancer-Causing Cells, Mutation

You May Already Have Billions of Cancer-Causing Cells

檢查方法 tumor marker

• Tumor marker
• CA 19-9 Blood Test (Pancreatic Cancer)

治療方法

化療(chemotherapy)和放療(radiation therapy)

• Understanding Platinum-Based Chemotherapy
• 化疗和放疗为什么不能治愈癌症？

Neoadjuvant therapy 新輔助療法

(cancer.gov) Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. It is a type of induction therapy.

Adjuvant therapy 輔助治療

(cancer.gov) Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy (Balversa - FDA approves first targeted therapy for metastatic bladder cancer), or biological therapy.

Immunotherapy

• As we age, cancer rates go up as immune system winds down
• CAR T-cell - Engineering Patients’ Immune Cells to Treat Their Cancers. Gene Therapy May Help Fight Tough-to-Treat Blood Cancer (multiple myeloma).
• Immunotherapy-chemo combo extends life for women with aggressive form of breast cancer. PD-L1 protein is responsible for telling the immune system “don’t attack me.”
• FDA approves first immunotherapy regimen for breast cancer Mar. 9, 2019
• 10 links about the basics of immunology

Phase of clinical trials

https://en.wikipedia.org/wiki/Phases_of_clinical_research

What Are the Different Types of Clinical Research? fda.gov

What Happens in a Clinical Trial? Phase III of a clinical trial usually involves up to 3,000 participants who have the condition that the new medication is meant to treat.

Demystifying Clinical Trials for Patients by Dr. Elise Kohn, Clinical Trials: What You Need to Know

What Are the Phases of Clinical Trials? cancer.org

• Phase I clinical trials: Is the treatment safe?
• Phase II clinical trials: Does the treatment work?
  • Usually, a group of 25 to 100 patients with the same type of cancer get the new treatment in a phase II study.
  • No placebo (sham or inactive treatments) is used.
• Most phase III clinical trials have a large number of patients, at least several hundred.
  • Placebos may be used in some phase III studies, but they’re never used alone if there’s a treatment available that works.
  • Phase III clinical trials: Is it better than what’s already available?

Basket trial

• FDA Modernizes Clinical Trials with Master Protocols.
• Clinical Trial Designs: Basket, Umbrella & Platform Trial Designs – Part II

A basket trial is a type of clinical trial that involves studying a single investigational drug or drug combination across multiple cancer populations. These populations can be defined by various factors such as disease stage, histology, number of prior therapies, genetic or other biomarkers, or demographic characteristics.

Basket trials offer a cost-effective option to evaluate targeted agents in multiple malignancies. They are designed with multiple arms, or "baskets", each representing a different malignancy or tumor site with the same target. This design allows for the evaluation of the efficacy of a targeted agent with fewer patients and in a shorter amount of time compared to traditional trial designs.

However, it's important to be aware of their limitations. For instance, molecular analyses and other tests need to be conducted only once in a basket trial, rather than multiple times if multiple traditional trials are conducted to answer the same question.

TILs/Tumor-infiltrating lymphocytes 腫瘤浸潤淋巴細胞

• https://en.wikipedia.org/wiki/Tumor-infiltrating_lymphocytes. TILs can often be found in the tumor stroma and within the tumor itself. Their functions can dynamically change throughout tumor progression and in response to anticancer therapy.
• Stromal and intratumoral. This paper Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.

胃腸道基質瘤

• Gastrointestinal stromal tumor
• 大腿2腫包.手臂見肉瘤！5種唇色看脾胃 中醫1茶飲疏肝散結！ 健康2.0.

基質瘤是從肌肉層的間質長出來的.

AYA/dolescent and young-adult

• Cancer in Youth Means Heightened Odds for Another Cancer Later
• AYAs had a higher risk of GC-specific death, indicating more attention should be paid into AYAs with GC. See Trend of gastric cancer incidence and death rate in adolescents and young adults 2023, and AYA Cancer Rates Are Rising, New Study Finds.

COVID

• Past History of Cancer Won't Make You More Vulnerable to Severe COVID
• Editorial to the special issue: statistical perspectives on analytics for COVID-19 data 2023

血液腫瘤科 Hematology oncology

• What Is a Hematologist Oncologist?. Types of blood cancers they might treat include:
  • Leukemia
  • Lymphoma
  • Multiple myeloma
• What Is Hematology Oncology?

IHC 免疫組織化學

https://en.wikipedia.org/wiki/Immunohistochemistry

Cancer cases/stat

https://seer.cancer.gov/statfacts/html/stomach.html

常見癌症

Ovarian 卵巢 cancer

Q: how doctors choose to give PARPi treatment to ovarian patients?
A: In the management of ovarian cancer, doctors make treatment decisions based on clinical guidelines, patient characteristics, and available evidence. Here are key considerations for prescribing PARPi (Poly (ADP-ribose) Polymerase Inhibitors) to ovarian cancer patients:

• Eligibility Criteria:
  • Newly Diagnosed Patients: For patients with newly diagnosed, stage III-IV, high-grade serous or endometrioid ovarian cancer who responded to first-line platinum-based chemotherapy, PARPi maintenance therapy is recommended. PS. PARPi is not a traditional chemotherapy. It is a targeted therapy, not a primary therapy (first-line treatment).
  • HRD Status: PARPis are effective in cancers with homologous recombination deficiency (HRD) caused by underlying etiologies other than BRCA mutations.
  • Prior Exposure: All approvals for PARPis are predicated on the absence of prior exposure to these drugs.
• Maintenance Therapy:
  • PARPi maintenance therapy is crucial for eligible patients.
  • Commonly used PARPis include olaparib, niraparib, and rucaparib.
  • Duration varies based on the specific PARPi and patient characteristics.
• Clinical Trials Participation
• Toxicity Management
• Individualized Approach

PARPi therapy (3 PARPi are now approved: rucaparib, olaparib, and niraparib) is only effective in specific situations, mainly with HRD-positive cancers.

• The HRD Decision—Which PARP Inhibitor to Use for Whom and When 2017, CCR.
• Appropriate Selection of PARP Inhibitors in Ovarian Cancer 2022, Gynecologic Cancers.
• The potential of PARP inhibitors in targeted cancer therapy and immunotherapy 2022.

Pancreatic Cancer

Drug Trio Improves Odds Against Advanced Pancreatic Cancer

Multiple Myeloma 多發性骨髓瘤

骨頭像被開洞！當心骨頭疼痛 健康2.0

Glioblastomas(GBM)膠質母細胞瘤

temozolomide (TMZ), Glioma 神經膠質瘤

• GBM是最常见、最恶性的膠質瘤，通常生长得非常快速且侵犯性强，且常常会在治疗后复发。
• 而神经膠質瘤是一类包括GBM在内的多种不同亚型的膠質瘤。与GBM相比，神经膠質瘤通常生长得更慢，但仍具有侵犯性和复发的趋势。
• MGMT指的是酶 O-6-甲基鳥嘌呤-DNA-甲基轉移酶（O-6-methylguanine-DNA methyltransferase），是一种由MGMT基因编码的蛋白质。MGMT酶在维护DNA稳定性和细胞修复机制中发挥着重要的作用。具体而言，MGMT酶能够修复DNA中的甲基化损伤，这种损伤可能会导致基因突变和肿瘤的发生。 在脑部肿瘤治疗中，MGMT通常被认为是一种预后标志物。在某些治疗方案中，例如放射治疗和化学治疗中，MGMT的表达水平可能会影响治疗的疗效和预后。例如，MGMT高表达(highly expressed)的患者通常对放疗和化疗的反应较差，因为MGMT酶可以修复这些治疗造成的DNA损伤，从而使肿瘤细胞更难被杀灭。因此，MGMT在脑部肿瘤治疗中是一个非常重要的分子标志物。
• MGMT stands for O-6-methylguanine-DNA methyltransferase, which is an enzyme that is encoded by the MGMT gene. MGMT plays an important role in maintaining DNA stability and cellular repair mechanisms. Specifically, MGMT is able to repair methylated 癌細胞 DNA damage, which can otherwise lead to gene mutations and the development of cancer. In brain tumor treatment, MGMT is often considered a prognostic biomarker. The expression levels of MGMT can impact the effectiveness of certain treatment strategies, such as radiation therapy and chemotherapy. For example, patients with high MGMT expression levels tend to have poorer responses to radiation and chemotherapy, as MGMT can repair the DNA damage caused by these treatments, making it more difficult to kill tumor cells. Therefore, MGMT is a critically important molecular marker in brain tumor treatment.
• MGMT methylation typically leads to lower gene expression (see the explanation below about the promoter). Methylation of the MGMT promoter region, which is a common epigenetic modification in some cancers, can lead to decreased expression of the MGMT gene and therefore lower levels of MGMT protein. This is because methylation of the promoter region can interfere with the binding of transcription factors and RNA polymerase, which are necessary for gene transcription and protein synthesis. 当MGMT的启动子(promoter)区域被甲基化(methylated)时，这会阻碍转录因子(transcription factor)和RNA聚合酶的结合，并使其难以识别MGMT的启动子区域，从而导致该基因的表达受到抑制。
• In brain tumor treatment, MGMT promoter methylation status is often used as a biomarker to predict treatment response. Tumors with methylated MGMT promoters tend to have lower levels of MGMT protein and are more sensitive to alkylating agents such as temozolomide, a chemotherapy drug used to treat brain tumors. This is because the DNA damage caused by temozolomide cannot be efficiently repaired in cells with low MGMT expression due to promoter methylation, resulting in increased sensitivity to the drug.
• (Video explanation) Patients that have MGMT methylation have a better prognosis because they don't make the MGMT enzyme in their tumor cells which can inactivate Temozolomide. In summary, overall prognosis/survival for patients is better for patients with Methylated MGMT vs Unmethylated MGMT. DNA methylation can inactivate a promoter region so if someone has methylation of the promoter region of their mgmt gene, then that means this gene is going to be inactivated so that will put a stop on this gene from being expressed. If a glioblastoma brain tumor is methylated, it means the MGMT protein is NOT being produced and therefore the molecule will not be removed from the guanine. If the molecule is not removed from the guanine, the chemotherapy has a greater effect.
• Temozolomide and MGMT Methylation, Apoptosis

大腸癌 & 十二指腸癌

健康2.0. 你知道有「這個基因突變」的人，有80%的機率得腸癌嗎

Genes

Related to cancer

• https://www.oncokb.org/cancerGenes
• Most cancers are not caused by genetic mutations
• Most Cancers Caused Mainly By 'Bad Luck' Mutations: Johns Hopkins Study
• 罹癌天註定？營養醫學博士教你：3個方法扭轉癌基因: 努力減少生活環境中的危險因子，以避免觸發致癌基因，也可積極借助營養醫學進行個人化營養療法來調控基因，幫助遠離癌症。

Anticancer drug resistance

Anticancer drug resistance: an update and perspective 2021

Druggable genes

Overview of Targeted Therapies for Cancer

Most notable genes present in the human genome

https://en.wikipedia.org/wiki/List_of_human_genes

House-keeping genes

• https://en.wikipedia.org/wiki/Housekeeping_gene
• Table with important Housekeeping Genes
• http://www.housekeeping.unicamp.br/?download
• Question: Is there a list of mouse housekeeping genes available to download?
• What are housekeeping genes?

Tumor suppressor gene

• The BRCA1 and BRCA2 proteins are important in maintaining genomic stability by promoting efficient and precise repair of double-strand breaks. The main role of BRCA2 appears to involve regulating the function of RAD51 in the repair by homologous recombination. See The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability
• BRCA1 and BRCA2 are tumour suppressor genes with a central role in the homologous recombination repair (HRR) pathway. HRR is the major pathway for the repair of double-stranded DNA breaks (DSBs). This is clinically important as failure of this pathway means that precision treatment options may be available for patients affected with BRCA-deficient cancers (e.g. PARP inhibitors). See BRCA1 and BRCA2.
• There are two main pathways that repair double-stranded DNA breaks (DSBs): Homologous recombination (HR) and Non-homologous end-joining (NHEJ).
• BRCA-deficient refers to cells that lack functional BRCA proteins due to mutations or defects in the BRCA1 or BRCA2 genes. These cells utilize error-prone DNA-repair pathways, causing increased genomic instability, which may be responsible for their sensitivity to DNA damaging agents and poly-(ADP)-ribose polymerase inhibitors (PARPis).

Immune genes

快遠離這些飲食習慣！會改變細胞的基因表現. NLRP3 gene

Pathogenicity

• When a gene is said to be related to the pathogenicity of a cancer, it means that alterations or mutations in that gene contribute to the development and progression of the cancer.
• There are two main types of genes that, when altered, can lead to cancer: oncogenes and tumor suppressor genes.
• How do we know a gene is pathogenic?
  • Genomic sequencing
  • Bioinformatic analysis
  • Variant interpretation
  • Functional studies
  • Population studies
  • Literature and database reviews

Oncogene

Oncogenes are genes that promote cell growth and reproduction.

TP53

The expression of TP53 is frequently altered in cancer. TP53 is commonly referred to as a tumor suppressor gene, meaning that its normal function is to help regulate cell division and prevent the formation of tumors. Mutations in TP53 are among the most common genetic changes in cancer, and are associated with a wide range of tumor types.

In some cancers, TP53 is altered through mutations that result in a loss of function, leading to increased cell growth and division, which can contribute to the development of a tumor. In these cases, the gene expression of TP53 may be decreased.

In other cancers, TP53 is overactive due to mutations that result in a gain of function, leading to increased cell death. In these cases, the gene expression of TP53 may be increased.

It's important to note that the specific expression patterns of TP53 can vary depending on the type of cancer and the stage of the disease, so it's not possible to make a blanket statement about the expression of TP53 in all cancer patients.

CD47

• CD47 is a protein that sits on the surface of cells and tells the body’s immune system not to eat (phagocytose) them. It’s like a “don’t eat me” sign. Now, in some drug-resistant diseases like certain types of cancer, the sick cells have more of this CD47 protein. This means they have a stronger “don’t eat me” sign and so they can avoid being destroyed by the body’s immune system. This is one way that they can survive and become resistant to drugs.
• CD47, an integrin-associated receptor, has been found to be significantly upregulated in drug-resistant myeloma cells compared to parental cells. High expression of CD47 detected by immunohistochemistry is associated with shorter progression-free and overall survivals in multiple myeloma patients1. Additionally, it has been reported that CD47 expression can be regulated by microRNAs (miRNAs). MiRNAs can regulate phagocytosis of macrophages, apoptotic process, drug resistance, relapse of disease, radio-sensitivity, and suppress cell proliferation, migration, and invasion through post-transcriptional regulation of CD47-SIRPα signaling axis.
• CD47, also known as Cluster of Differentiation 47 or integrin associated protein (IAP), is a transmembrane protein that is encoded by the CD47 gene in humans. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins. It also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα).

Genes in news

• IRF4 gene and gray hair
• Single Gene Responsible for Group of Heart Disease Risk Factors and The Unexpected Way Genes Can Double Heart Disease Risk
• FDA Panel Recommends Approval of the First Gene Therapy Treatment
• FDA Approves DNA Test to Spot Cancer Genes — But With Warnings
• Astronaut's DNA no longer matches that of his identical twin, NASA finds
• 癌細胞惡化轉移基因 中研院找到了 致癌基因 PSPC1
• OSER1 基因 Newly Discovered Gene Could Be the Secret to Longevity
• Most Women With Breast Cancer Can Skip Chemo:
  • Oncotype DX, which examines the activity of 21 genes to predict the risk of a recurrence over 10 years.
  • TIME (no links to the source),
  • cnn which includes the source of the news.
  • nytimes which includes the source of the news and good info.
  • WashingtonPost which includes the source and good info.
• One Gene Change 2 Million Years Ago Left Humans Vulnerable to Heart Attack CMAH (now called CMAHP)
• A Gene Kept One Woman From Developing Alzheimer's -- Could It Help Others? PSEN1
• Global Consortium Finds Genes That Drive Severe COVID-19. FOXP4, DPP9, TYK2. Inhibiting such genes could be potential treatments for preventing severe COVID-19.
• The study also found that the gene for a protein called PLA2G7 was significantly inhibited in participants who restricted their calorie intake. Cutting Calories Could Extend Your Life
• Gene Test Lets Some Colon Cancer Patients Safely Skip Chemo. Circulating tumor DNA (ctDNA) test.
• PCNA. AOH1996 a chemotherapy drug. 美國「AOH1996」問世 有望成癌症治療新藥

Breast cancer

• https://en.wikipedia.org/wiki/Breast_cancer, https://en.wikipedia.org/wiki/Breast_cancer_classification#Receptor_status
  • estrogen receptors (ER+) and progesterone receptors (PR+)
  • Breast cancer cells have receptors on their surface and in their cytoplasm and nucleus. Chemical messengers such as hormones bind to receptors, and this causes changes in the cell.
  • Breast cancer cells may or may not have three important receptors: estrogen receptor (ER)雌激素受體, progesterone receptor (PR)孕酮受體, and HER2表皮生長因子受體-2.
  • ER+ cancer cells (that is, cancer cells that have estrogen receptors) depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g. tamoxifen), and generally have a better prognosis.
  • 超過10%乳癌患者的TP53、PIK3CA和GATA3基因有突變。
• 三陰性乳癌是什麼？看懂三陰性乳癌的成因、症狀及治療新藥

• Generally, after surgery, such patients receive endocrine therapy, such as tamoxifen, which is designed to block the cancer-spurring effects of hormones.

• Take a closer look at biomarkers to better understand your patients’ disease
  • HR and HER2 are prognostic biomarkers
  • HR-positive disease is the most common subtype and results in the majority of breast cancer deaths
  • BRCA is another biomarker that can provide you with additional valuable information

健康2.0世紀論壇

• 《防癌保胃戰》, Median overall survival months t0 is calculated P(T >= t0) =0.5. Patient-derived tumor xenografts
• 慢性胃炎、胃萎縮到胃癌… 三部曲要你命

Proteins

• https://en.wikipedia.org/wiki/Protein
• Types:
  • Enzymes: as we mentioned earlier, enzymes are proteins that catalyze chemical reactions in the body.
  • Structural proteins: these proteins provide support and structure to cells and tissues. Examples include collagen, elastin, and keratin.
  • Transport proteins: these proteins help to transport molecules and ions across membranes, such as hemoglobin, which transports oxygen in the blood.
  • Hormones: these proteins act as signaling molecules and help to regulate various bodily processes, such as insulin which regulates glucose metabolism.
  • Antibodies: these proteins play an important role in the immune system by recognizing and neutralizing foreign substances, such as viruses and bacteria.
  • Contractile proteins: these proteins enable muscles to contract, allowing for movement in the body. Examples include actin and myosin.
  • Storage proteins: these proteins store important molecules in the body, such as ferritin, which stores iron in the liver.

Drugs

• Search fda, drug name and label in google/bing.
  • PDF document Olaparib/LYNPARZA. Pay attention to section 14 (Clinical studies) & section 6 Adverse reactions (safety).
• https://www.fda.gov/drugs.
  • Search "Olaparib". Article .
• ClinicalTrials.gov

Drug/therapy categories

An overview of common drug categories

Simplified Framework

Category	Primary Function Mechanism of Action	Examples
Chemotherapy	Kill rapidly dividing cells	Temozolomide(TMZ), Cisplatin
Targeted Therapy	Block specific molecular targets	Imatinib, Bevacizumab
Immunotherapy	Activate the immune system	Pembrolizumab, Ipilimumab
Hormonal Therapy	Alter hormone levels or activity	Tamoxifen, Abiraterone
Supportive Care	Manage symptoms or treatment side effects	Ondansetron, Filgrastim
Miscellaneous	Antibiotics, HDAC Inhibitors, Anti-Epileptics	dactinomycin or mitomycin C, VPA, LEV

Additive vs synergistic drug effect

• Types of Drug-Drug Interactions
• Additive effect

GI50

• GI50 represents the concentration of a test agent, such as a drug, that results in inhibiting cell growth by 50%.
• What is the definition of cell growth by 100%? Cell growth is the process by which cells increase in size and number. 100% cell growth would mean that the cells have doubled in number.
• How do I measure cell growth in vivo? One way to measure cell growth in vivo is by pulse-labeling tissues with BrdU before harvesting, followed by assessing BrdU by ELISA or immunohistochemical staining. This can also be assessed by flow cytometry 流式細胞術. See Tests used on biopsy and cytology specimens to diagnose cancer.

Gene expression

• Identify genes whose baseline expression levels are related to drug response. These genes are often referred to as predictive biomarkers, as they can help predict how an individual will respond to a particular drug or treatment. Identifying such biomarkers can have several important implications:
  • Personalized Medicine: Predictive biomarkers can help in the development of personalized treatment strategies. By identifying patients who are likely to respond well to a particular drug, healthcare providers can tailor treatment plans to individual patients, potentially improving treatment outcomes and reducing the risk of adverse effects. 新的病人只有baseline expression, 沒有drug treated expression. "predict" 字可以被使用.
  • Drug Development: Understanding the genes that are related to drug response can provide insights into the underlying mechanisms of drug action and resistance. This information can be valuable in the development of new drugs and treatment strategies.
  • Clinical Trials: Biomarkers can be used as inclusion criteria or stratification factors in clinical trials, helping to identify patient subgroups that are more likely to benefit from a particular treatment. This can improve the efficiency and cost-effectiveness of clinical trials.
  • Monitoring Treatment Response: Biomarkers can also be used to monitor treatment response over time. Changes in the expression levels of these genes during treatment can provide insights into the effectiveness of the treatment and help guide treatment decisions.
  • Papers: Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines 2014.
  Overall, identifying genes whose baseline expression levels are related to drug response can provide valuable insights that can inform clinical decision-making and improve patient outcomes. Remember, while this approach can be very informative, it’s also complex. Factors such as the patient’s overall health, the presence of other medications, and environmental factors can also influence drug response. Therefore, it’s important to consider these factors in any analysis.
• Finding genes whose drug-induced gene expression profiles/changes are related to drug response can also be valuable in understanding the mechanisms of drug action and identifying potential biomarkers for predicting drug response. This approach can provide insights into how the drug affects biological processes and pathways relevant to the disease, as well as identify genes that may play a role in determining whether an individual will respond favorably to the drug. "predict" 字不可被使用.
  • By identifying genes that show differential expression in responders compared to non-responders following drug treatment, researchers can gain insights into the molecular mechanisms underlying drug response and resistance. These genes may be involved in pathways related to drug metabolism, drug transport, drug targets, or downstream effects on cellular processes.
  • Identifying such genes can also lead to the development of biomarker panels that can be used to predict drug response in clinical settings. These biomarkers can help clinicians make informed decisions about treatment selection and dosing, potentially leading to more effective and personalized treatment strategies.
  • Papers: Drug-Induced Regulation of Target Expression 2010.
  In summary, identifying genes whose drug-induced expression changes are related to drug response can provide valuable insights into the mechanisms of drug action and resistance, as well as lead to the development of predictive biomarkers for guiding clinical decision-making in the context of personalized medicine.

Research, videos

• https://datascience.cancer.gov/news-events/events (CBIIT)
• https://videocast.nih.gov/
• https://bioinformatics.ccr.cancer.gov/btep/btep-video-archive-of-past-classes/
• NCI Containers and Workflows Interest Group (CWIG)
• https://www.cancerimagingarchive.net/collections/
• NCI at Frederick. Batch effect corrections, Git/Jenkins, Pvalue, Missing data, Sample size/Statistical power, Containers.