Hallmarks of a Cancer Cell

The Hallmarks of Cancer

were proposed as a set of functional capabilities acquired by human cells as they make their way from normalcy to neoplastic growth states, more specifically capabilities that are crucial for their ability to form malignant tumors

Oncogene

a gene whose product protein is involved in either transforming cells in tissue culture or in inducing cancer in animals.Most oncogenes are mutant forms of normal genes in control of cell growth or division

Oncogenic (mutant) Ras proteins

are hyperactivated forms of Ras, and are the most common genetic alterations detected in human cancer. Classified as a cancer driver mutation.

90%

What % of human pancreatic cancers are driven by abnormal oncogenic Ras signaling?

Ras

represents a gene/protein product that when activated commits a cell to S-phase(DNA synthesis) of cell cycle when it should normally abort and undergo apoptosis

H, K, N

What are the 3 diff types of Ras proteins?

KRAS G12C

one of the most frequent KRAS mutations, locks the KRAS protein in a activated state leading to increased cellular signaling and unchecked tumor growth

Panitumumab (VECTIBIX)

Cetuximab (ERBITUX)

What are the therapeutics that target EGFR-RAS signaling?

chimeric MAb

Cetuximab (ERBITUX)

Human MAb

Panitumumab (VECTIBIX)

Panitumumab (VECTIBIX) and Cetuximab (ERBITUX)

• Both indicated for metastatic colorectal cancer (mCRC)—administered by infusion --in combination with FOLFOX regimen (Folinic acid; Flurouracil; Oxaplatin) -

• In July 2009, the FDA approved labeling changes to VECTIBIX and ERBITUX stating that these agents are not recommended for the treatment of CRC harboring KRAS mutations. Thus, determination of KRAS mutation status in patients is critical when evaluating their eligibility for anti-EGFR therapy.

• Mutations in the KRAS gene, present in about 40% of CRC patients, are associated with poor prognosis and lack of response to anti-epidermal growth factor receptor (anti-EGFR) therapy

Patients are genotyped (tissue biopsy) in advance -to see if they are candidates for these drugs

What has to happen in advance to giving Panitumumab (VECTIBIX) and Cetuximab (ERBITUX)?

KRAS

the holy grail target protein

give Sotorasib or adagrasib

What do we do with patients that harbor a KRAS mutation?

LUMAKRAS (sotorasib)

-Approved May 2021

-FDA granted Fast track, First-In-Class, Priority Review, Breakthrough, Orphan Drug designations

-Dose: 960 mg QD

-covalent inhibitor of the KRAS G12C mutation

KRAZATI (adagrasib)

-Approved Dec 2022

-Dose: 600 mg BID

-covalent inhibitor of the KRAS G12C mutation

Sotorasib and Adagrasib

-Both indicated in combination* for locally advanced or metastatic CRC in-patients that have previously received prior systemic cancer treatment...and harbor the G12C KRAS mutation. Second-line therapy.

*sotorasib + panitumumab

*adagrasib + cetuixmab

-By combining KRAS and EGFR inhibitors, the cancer cells are less likely to develop resistance to the KRAS inhibitor, and the EGFR pathway is also blocked, leading to a more significant and durable response. Wowza!

13%

What % of people with NSCLC have the KRAS G12C mutation?

Daraxonrasib

-available in the US to pts ahead of FDA approval

-doubled median overall survival vs standard chemo

-the worse the rash the better the survival

G1/S checkpoint

-is the primary regulator of the cell cycle and essential for advancement of malignant tumors

-This checkpoint is regulated by a protein (cyclin D) and enzymes (cyclin dependent kinases) CDK 4/6

Cyclin-CDKs

regulate cell cycle by phosphorylating target proteins

Rb primary function

is to act as a tumor suppressor protein and bind to and inactivate E2F transcription factors

E2F factors

important proteins that bind to DNAand activate genes which control the cell cycle and DNA replication, including the cyclinsand CDKs specific to G1 and S phases of the cell cycle

off

Rb keeps the cell in check by turning ____ gene expression.

inactivates

In cancer cells, hyper-phosphorylation of Rb by CDK/cyclin __________ Rb which releases E2F to act as a transcriptional activator, and gene expression is turned on. This is one way a cancer cell turns off tumor suppressor proteins.

Palbociclib (IBRANCE)

-CDK inhibitor

-first in class and selective inhibitor of cyclin dependent kinases (CDK) 4/6

-approved Feb 2015

-Indicated for treatment of breast cancer and other cancers; more on this class of targeted therapeutics later

apoptosis

-programmed cell death

-represents a normal part of cell life

-serves as a natural barrier to cancer development

off

Cancer cells turn ____ apoptotic signals and this allows them to survive.

key

Driving cancer cells to commit apoptosis is the ________!!! do this in the mitochondria

necrosis

-stimuli: pathologic "cell homocide"

-histology: large #s cells, swelling, acidosis, liquefaction

-DNA-breakdown: random, diffuse-fragmtxn, nuclear dissolution

-tissue RxN: inflammation and surrounding normal tissue damage

apoptosis

-stimuli: physiologic "cell suicide

-histology: few cells, shrinkage, apoptotic bodies

-DNA-breakdown: orderly nuclear condensation and fragmentation

-Tissue RxN: no inflammation, no secondary tissue damage

VENCLEXT

-an apoptosis inducer

-is approved for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL),with or without 17p deletion, following at least 1 prior therapy.This deletion involves the loss of the TP53 tumor suppressor gene

-oral, take with meal/water

Warnings and Precautions

- Tumor Lysis Syndrome (TLS)

- Neutropenia

- Infections

senescent

loss of the ability to divide

indefinitely

Cancer cells divid ___________

loss of telomerase activity

What causes senescence?

they can reactivate telomerase and become immortal

How do cancer cells avoid senescent?

telomere

is a repeating sequence (GGTTAG) of double-stranded DNA located at theends of chromosomes. Greater telomere length is associated with immortalized celllines such as embryonic stem cells and cancer cells

shortened

As cells divide and differentiate throughout the lifespan of an organism or cell line, the telomeres become progressively __________ and lose the ability to maintain their length.

telomerase

is a reverse transcriptase that lengthens telomeres by adding on repeating sequences of DNA by using a hairpin RNA as a template

over 90%

What % of cancers have the hallmark of telomere maintenance and high telomerase activity?

shorter

Tumors generally have _________ telomeres than the surrounding normal tissue, owing to the fact that they have had a longer proliferative history in the absence of telomerase activity. However, telomerase is reactivated in more than 90% of all types of human tumors.

angiogenesis

-formation of new blood vessels (vascularization)

-Normal physiological process involved in embryo development, wound healing, organ perfusion

Angiogenesis Inhibitors

block key growth factors or their receptors (e.g.,VEGF) involved in promoting angiogenesis or by blocking angiogenic signaling pathways

AVASTIN (bevacizumab)

-angiogenesis inhibitor

-Boxed Warnings:Gastrointestinal Perforation in 3%patients, Surgery and WoundHealing Complications,Hemorrhage

overt metastasis

is the final manifestation of a series of events collectively known as the 'metastatic cascade

HGF/c-Met pathway

is an important contributor tumor cellproliferation, survival, invasion, and metastasis

c-Met

is overexpressed, activated, amplified, or mutated in a wide variety of solid tumors, is correlated with poor prognosis and is thought to contribute to a tumor's aggressiveness and resistance to therapy

OMETRIQ (cabozantinib)

• Indicated for metastatic medullary thyroid cancer (mMTC)

• Is a potent inhibitor of c-Met and vascular endothelial growth factor receptor-2 (VEGFR2)

• Dual acting drug!

- Anti-angiogenic

- Anti-metastatic

• Boxed Warnings similar to other VEGF blockers (GI perforations, hemorrhage)

PARP Inhibitors and BRCAmutations: Synthetic Lethality

-Only in patients with BRCAvmutations (which lack HR repair pathways), PARP inhibitors lead to cancer cell death!

-Concept of Synthetic Lethality

re-awaken immune system with cancer immunotherapies

What is a way to fix cancer cells avoiding immune destruction?

CTLA-4 and PD-1 pathways

are immune checkpoint pathwaysthat play critical roles in controlling T-cell immune responses

Anti-CTLA-4, PD-1, or PD-L1 antibodies

can restoreT-cell activation and killing of tumor cells

Keytruda and Opdivo

tumor/tissue agnostic drugs