Molecular and Cell biology Exam #4

What is the best strategy for cancer prevention?

Prevent cancer before it develops.

What is the second-best strategy for cancer treatment?

Detect premalignant or early-stage tumors before metastasis.

What is the five-year survival rate for localized carcinomas?

~90%

What is the five-year survival rate for metastatic colon cancer?

~15%

Which mutations are associated with inherited cancer susceptibilities?

Mutations in tumor suppressor genes (e.g., BRCA1, BRCA2) and stability genes.

What preventive measure may women with BRCA mutations undergo?

Prophylactic mastectomy or oophorectomy.

What is the role of genetic testing in cancer prevention?

It can identify high-risk individuals before disease onset.

What is the incidence of hereditary nonpolyposis colon cancer in the U.S.?

~15% of colon cancers, 1-2% of all cancers.

What are oncogene-targeted drugs designed to do?

Selectively inhibit cancer-driving pathways while sparing normal cells.

What is a major drawback of traditional chemotherapy?

It damages both cancer cells and normal proliferative cells, causing severe side effects.

What is Herceptin (trastuzumab) used for?

It targets the ErbB-2 receptor tyrosine kinase in breast cancer.

What is Gleevec (imatinib) effective against?

Chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs).

What mutation is targeted by Vemurafenib?

B-Raf V600E mutation found in ~60% of melanomas.

What is the significance of the EGFR inhibitors gefitinib and erlotinib?

They are effective in lung cancer patients with EGFR point mutations.

What is the concept of oncogene addiction?

Tumors with activated oncogenes become dependent on them for survival and proliferation.

What is the clinical significance of Lumakras (sotorasib)?

It targets the RasK G12C mutation, marking a major advance in lung cancer treatment.

What is the role of monoclonal antibodies in targeted therapies?

They target extracellular domains of receptors (e.g., Herceptin, Erbitux).

What are small molecule inhibitors designed to do?

They target intracellular kinases and signaling proteins.

What is the impact of genetic profiling of tumors?

It is essential to identify patients who will benefit from specific targeted therapies.

What is the five-year survival rate for regional spread of cancer?

~70%

What is the mechanism of action for MEK inhibitors?

They block downstream signaling in the ERK/MAPK pathway.

What is the mechanism of action for mTOR inhibitors?

They block mTOR kinase, a central regulator of growth and metabolism.

What are Cdk4/6 inhibitors used for?

They block cell cycle progression at the G1 restriction point.

What is the role of PI3K inhibitors in cancer treatment?

They target PI3K oncogene activity.

What are the challenges of oncogene-targeted therapy?

General inhibition of oncogene activity risks harming normal cells.

What is the promise of targeted therapies?

More precise, less toxic treatments that exploit specific molecular defects in cancer cells.

What is the future direction for cancer prevention and early detection?

Expanding identification of susceptibility genes to improve prevention and reduce mortality.

What is the role of oncogenes in cancer?

Oncogenes drive abnormal cell proliferation by increasing gene expression or protein hyperactivity due to mutations, amplifications, or translocations.

How do tumor suppressor genes function?

Tumor suppressor genes normally act as negative regulators of cell proliferation and tumor development; their inactivation or loss contributes to malignancy.

What is oncogene addiction?

Oncogene addiction refers to the dependence of tumors on specific mutations for their growth and survival.

What are common mechanisms of resistance to oncogene-targeted therapies?

Mechanisms include mutations in the targeted kinase, activation of alternative tyrosine kinases, and activation of downstream pathways.

What is the significance of combining multiple targeted therapies?

Combining multiple targeted therapies is a major research focus to prevent or overcome resistance in cancer treatment.

What is the goal of immunotherapy in cancer treatment?

The goal is to strengthen the immune system's ability to recognize and destroy cancer cells.

What are immune checkpoint inhibitors (ICIs)?

ICIs are antibodies that block checkpoint receptor-ligand interactions, restoring T-cell activation and enhancing the immune attack on cancer cells.

What was the impact of CTLA-4 blockade in cancer therapy?

CTLA-4 blockade led to the FDA approval of ipilimumab for metastatic melanoma, achieving durable remission in ~20% of patients.

What is the function of the Rb gene?

The Rb gene acts as a tumor suppressor, and its loss is linked to tumorigenesis, particularly in retinoblastoma.

What is Knudson's Two-Hit Hypothesis?

It states that tumor development requires two mutations (loss of both Rb alleles), explaining inherited and sporadic cases of retinoblastoma.

What is the prevalence of p53 mutations in human cancers?

The p53 gene is mutated in approximately 50% of all human cancers, making it the most common genetic target in malignancy.

How do BRCA1 and BRCA2 mutations relate to cancer?

Inherited mutations in BRCA1 and BRCA2 are linked to hereditary breast cancer, accounting for about 5% of cases.

What is the role of CAR-T cell therapy?

CAR-T cell therapy involves engineering T cells to express chimeric antigen receptors that recognize and destroy cancer cells.

What are the challenges of CAR-T therapy in solid tumors?

Solid tumors often have heterogeneous surface markers, complicating CAR design and tumor clearance compared to uniform B-cell cancers.

What is the significance of genomic profiling in cancer treatment?

Genomic profiling helps identify specific oncogene mutations, guiding tailored treatment in personalized medicine.

What are the FDA-approved anti-PD-1 therapies?

Nivolumab (Opdivo) and pembrolizumab (Keytruda) are FDA-approved for melanoma and other cancers.

What is the mechanism of action of immune checkpoint inhibitors?

ICIs block inhibitory interactions between checkpoint receptors and their ligands, releasing the 'brakes' on T cells.

What is the role of monoclonal antibodies in immunotherapy?

Monoclonal antibodies target oncogene proteins on cell surfaces to enhance the immune response against cancer cells.

What is the historical significance of the Rb gene?

The Rb gene was the first tumor suppressor gene identified, establishing the principle that loss of both functional copies is required for cancer development.

What types of cancers are associated with p53 mutations?

p53 mutations are associated with various cancers, including leukemias, lymphomas, sarcomas, and carcinomas of the breast, colon, and lung.

What is the impact of genetic engineering in immunotherapy?

Genetic engineering enhances immune responses, exemplified by CAR-T cell therapy, which reprograms T cells to attack tumors.

What is the therapeutic strategy behind PD-L1 inhibitors?

PD-L1 inhibitors target the ligand that activates PD-1, enhancing the immune response against cancer cells.

What is the dual imbalance in cancer development?

Cancer arises from the combined effects of oncogene activation and tumor suppressor gene loss.

What is the significance of the 2018 Nobel Prize in Physiology or Medicine?

The prize was awarded to James Allison and Tasuku Honjo for their pioneering work on immune checkpoint inhibitors.

What are the implications of tumor suppressor gene inactivation?

Inactivation or loss of tumor suppressor genes removes growth control, contributing to the development of malignancies.

What are BRCA1 and BRCA2 associated with?

Inherited mutations causing hereditary breast cancer (~5% of cases).

How many tumor suppressor genes are implicated in human cancer?

More than 50 tumor suppressor genes.

What is the primary function of tumor suppressor proteins?

To inhibit proliferation and survival.

What happens when tumor suppressors are lost?

Negative regulation is eliminated, allowing oncogenes to dominate.

What is the function of PTEN?

A lipid phosphatase that dephosphorylates PIP3 and antagonizes PI 3-kinase/Akt signaling.

What is the significance of PTEN loss?

Increased PIP3 leads to Akt activation and inhibition of apoptosis.

What dual imbalance leads to cancer development?

Activation of oncogenes and inactivation of tumor suppressors.

What is the role of Smad tumor suppressor genes?

Encode transcription factors activated by TGF-β signaling to control proliferation.

What does the Rb protein do?

Inhibits passage through the restriction point in G1 and represses transcription of cell cycle progression genes.

How does p53 contribute to cancer prevention?

Regulates cell cycle progression and apoptosis in response to DNA damage.

What happens when p53 is mutated?

Loss of DNA damage checkpoint leads to genetic instability and therapy resistance.

What is the function of BRCA1 and BRCA2 genes?

Involved in checkpoint control and repair of double-strand DNA breaks.

What is the role of miRNAs in cancer?

Post-transcriptional regulators that can inhibit translation or promote mRNA degradation.

What is the impact of lower miRNA expression in tumors?

Suggests tumor suppressor roles for those miRNAs.

What are lncRNAs and their role in cancer?

Long non-coding RNAs that can act as either oncogenes or tumor suppressors.

What is the significance of genome sequencing studies in cancer?

Identified ~150 genes mutated in human cancers, with half being oncogenes and half tumor suppressors.

What are driver genes in cancer?

A subset of genes that are consistently altered in specific cancer types.

What is the role of oncogenes?

Genes capable of inducing cancer by driving cell proliferation and survival.

What is the prototype of highly oncogenic retroviruses?

Rous sarcoma virus (RSV).

What is the src oncogene known for?

Encoding a 60-kDa tyrosine kinase required for cell transformation.

How do viral oncogenes relate to host cell genes?

Viral oncogenes are derived from host cell genes and are not needed for viral replication.

What is the function of the INK4 (p16) gene?

Encodes a Cdk inhibitor that blocks Cdk4/6-cyclin D complexes.

What is the consequence of p16 loss?

Elevated Cdk activity leads to continuous Rb phosphorylation and unchecked cell cycle progression.

What is the role of TGF-β receptors in cancer?

Act as tumor suppressors consistent with their role in growth inhibition.

What is the relationship between oncogenes and tumor suppressors?

Oncogenes promote cell growth, while tumor suppressors inhibit it.

What is the effect of MDM2 overexpression on p53?

It lowers p53 levels, enhancing cell proliferation and survival.

What is the role of the abl oncogene?

The abl oncogene drives transformation in cells.

What did Varmus and Bishop demonstrate about viral oncogenes?

They showed that viral oncogenes are derived from cellular proto-oncogenes.

Define proto-oncogenes.

Normal cell genes related to viral oncogenes that encode proteins controlling cell proliferation.

What distinguishes oncogenes from proto-oncogenes?

Oncogenes are mutated or abnormally expressed forms of proto-oncogenes that drive uncontrolled proliferation.

How do viral oncogenes differ in regulation from proto-oncogenes?

Viral oncogenes are regulated by viral promoters/enhancers, not normal regulatory sequences.

What is a key insight from the study of retroviruses?

Oncogenes are hijacked versions of normal cellular proto-oncogenes, linking viral and nonviral cancer research.

Who first demonstrated that human tumors contain cellular oncogenes?

Geoffrey Cooper and Robert Weinberg in 1981.

What is the significance of the ras oncogene?

It is the first human oncogene identified and is found in ~30% of all human cancers.

What mutations are commonly associated with ras oncogenes?

Point mutations at codons 12, 13, or 61.

What is the effect of mutations in ras proteins?

They lock Ras in the active GTP-bound state, leading to continuous signaling and uncontrolled proliferation.

Describe the mechanism of chromosome translocations in oncogene activation.

Translocations can alter gene expression or create abnormal fusion proteins with deregulated activity.

What is the effect of the c-myc translocation in Burkitt's Lymphoma?

It places c-myc under immunoglobulin promoter control, leading to unregulated expression and B lymphocyte proliferation.

What is the result of the bcr/abl translocation in Chronic Myeloid Leukemia?

It creates a fusion gene bcr/abl that produces a protein with unregulated tyrosine kinase activity.

How does DNA amplification contribute to oncogene activation?

It increases the number of copies of proto-oncogenes, leading to elevated expression.

What are some examples of oncogenes that undergo amplification?

c-myc, N-myc, L-myc, and erbB-2 (HER2).

What is the role of oncogenes in growth factor signaling?

They regulate normal cell proliferation; when hyperactive, they drive uncontrolled growth.

What is autocrine growth stimulation?

When a tumor cell produces a growth factor to which it also responds, leading to continuous self-stimulation.

How can growth factor receptors act as oncogenes?

Through chromosome translocation, gene amplification, or point mutations causing unregulated activity.

What is the function of Ras proteins in signal transduction?

They couple growth factor receptors to Raf kinase and mutations lead to constitutive ERK activation.

What is the role of transcription factor oncogenes like fos and jun?

They drive cyclin D expression, contributing to uncontrolled proliferation.

How does the Wnt pathway relate to oncogenesis?

Mutations stabilize β-catenin, leading to activation of target genes that promote unregulated proliferation.

What is the significance of cyclin D1 as an oncogene?

It drives proliferation without growth factor stimulation when activated by translocation or amplification.