NOVEL CANCER THERAPIES 2; SMALL MOLECULES AND SIGNALLING PATHWAYS

Question 1

AREA FOCUSED ON DEVELOPING PERSONALISED THERAPY FOR CANCER

Answer 1

PRECISION ONCOLOGY

Question 2

SMALL MOLECULE INHIBITORS FOR CANCER THERAPY PRIMARILY TARGET:

Answer 2

KINASES

Question 3

WHAT ARE THE SMALL MOLECULE INHIBITORS FOR TARGETED CANCER THERAPY?

Answer 3

1) TYROSINE KINASE INHIBITORS; RECEPTOR TYROSINE KINASE INHIBITORS AND NON-RECEPTOR TYROSINE KINASES
2) SERINE/THREONINE KINASE INHIBITORS (E.G. BRAF/MEK/ERK INHIBITORS, CDK INHIBITORS, PI3K/AKT/mTOR INHIBITORS
3) EPIGENETIC INHIBITORS (E.G. HISTONE METHYLTRANSFERASE INHIBITORS, HISTONE DEACETYLASE INHIBITORS, DNA METHYLTRANSFERASE INHIBITORS
4) PROTEOSOME INHIBITORS (BLOCK THE UBIQUITIN-PROTEASOME PATHWAY RESPONSIBLE FOR PROTEIN DEGRADATION AND THE PRODUCTION OF GROWTH-PROMOTING PROTEINS
5) BCL-2 INHIBITORS - PROMOTE APOPTOSIS
6) PARP INHIBITORS (DNA REPAIR PATHWAYS, SYNTHETIC LETHALITY IN FAMILIAL AND SPORADIC TUMOURS)

Question 4

WHICH PROCESS DO BCL-2 INHIBITORS TARGET SPECIFICALLY?

Answer 4

APOPTOSIS (PROMOTE IT IN CANCER CELLS, SMALL MOLECULE INHIBITION TARGETED TREATMENT)

Question 5

WHEN WAS THE FIRST KINASE INHIBITOR FOR CANCER TREATMENT APPROVED?

Answer 5

2001

Question 6

KINASES FUNCTION?

Answer 6

A kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule.

Question 7

GEFITINIB (IRESSA): WHAT IS IT AND WHAT IS IT USED FOR?

Answer 7

The active substance in Iressa, gefitinib, is a protein-tyrosine-kinase inhibitor. This means that it blocks specific enzymes known as tyrosine kinases. These enzymes can be found on the surface of cancer cells, such as EGFR on the surface of non-small-cell-lung-cancer cells. EGFR is involved in the growth and spread of cancer cells. By blocking EGFR, Iressa helps to slow down the growth and spread of the cancer. Iressa works only in non-small-cell-lung-cancer cells that have a mutation in their EGFR.

Iressa is used to treat adults who have non-small-cell lung cancer that is locally advanced or metastatic (when cancer cells have spread from the original site to other parts of the body). It is used in patients whose cancer cells have a mutation in the genes that make a protein called epidermal-growth-factor receptor (EGFR).

• SOME PATIENTS WITH REFRACTORY NSCLC THAT FAIL OR CEASE TO RESPON TO CHEMOTHERAPY SHOW DRAMATIC RESPONSE TO GEFITINIB (SOMETIMES LARGE MASSES CAN REGRESS IN AS LITTLE AS 6 WEEKS)
• A SUBSTANTIAL PROPORTION OF NSCLCs THAT RESPOND TO GEFITINIB CARRY DELETIONS AND POINT MUTATIONS IN THE EGFR

Question 8

SIDE EFFECTS OF TREATMENT WITH GEFITINIB AND OTHER EGFR INHIBITORS?

Answer 8

TREATMENT RESULTS IN THE DEVELOPMENT OF ACNE-LIKE RASH WHICH IS A POSITIVE INDICATOR OF THE RESPONSE OF TUMOUR THERAPY (AND IT REFLECT THE ROLE OF EGFR IN SKIN KERATINOCYTE BIOLOGY; the primary type of cell found in the epidermis, the outermost layer of the skin)

Question 9

NON SMALL CELL LUNG CANCER?

Answer 9

About 80% to 85% of lung cancers are NSCLC. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. These subtypes, which start from different types of lung cells are grouped together as NSCLC because their treatment and prognoses (outlook) are often similar.

Question 10

CHRONIC MYELOGENOUS LEUKAEMIA (CML)

Answer 10

• A MALIGNANT CANCER OF THE BONE MARROW
• CAUSES RAPID GROWTH OF THE BLOOD-FORMING CELLS; MYELOID PRECURSORS, IN THE BONE MARROW, PERIPHERAL BLOOD AND BODY TISSUES
• REPRESENTS ABOUT 14% OF ALL OCCURENCES IN LEUKAEMIAS
• CCA 700 CASES PER YEAR IN THE UK, MEDIAN AGE 55

Question 11

PHILADELPHIA CHROMOSOME?

Answer 11

An abnormality of chromosome 22 in which part of chromosome 9 is transferred to it (CHROMOSOMAL TRANSLOCATION RESULTING IN A FUSION OF BCR FROM CHROMOSOME 9 AND ABL FROM CHROMOSOME 22). Bone marrow cells that contain the Philadelphia chromosome are often found in chronic myelogenous leukemia (CML) and sometimes found in acute lymphocytic leukemia.

A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The BCR-ABL gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.

Question 12

IMATINIB (GLEEVEC) for CML?

Answer 12

Glivec is an anticancer medicine. It is used to treat the following diseases:

chronic myeloid leukaemia (CML), a cancer of the white blood cells in which granulocytes (a type of white blood cell) start growing out of control. Glivec is used when the patients are ‘Philadelphia chromosome positive’ (Ph+). This means that some of their genes have re-arranged themselves to form a special chromosome called the Philadelphia chromosome. Glivec is used in adults and children who have been newly diagnosed with Ph+ CML and who are not eligible for a bone marrow transplant. It is also used in adults and children in the ‘chronic phase’ of the disease if it is not responding to interferon alpha (another anticancer medicine), and in more advanced phases of the disease (‘accelerated phase’ and ‘blast crisis’)

The active substance in Glivec, imatinib, is a protein-tyrosine kinase inhibitor. This means that it blocks some specific enzymes known as tyrosine kinases. These enzymes can be found in some receptors on the surface of cancer cells, including the receptors that are involved in stimulating the cells to divide uncontrollably. By blocking these receptors, Glivec helps to control cell division.

• HAS A GREAT IMPACT ON SURVIVAL IN PATIENTS WITH CML

Question 13

APART FROM FOR CML, EXAMPLE OF WAY GLEEVEC CAN BE USED FOR?

Answer 13

gastrointestinal stromal tumours (GISTs), a type of cancer (sarcoma) of the stomach and bowel, when there is uncontrolled growth of cells in the supporting tissues of these organs. Glivec is used to treat adults with GIST that cannot be removed with surgery or have spread to other parts of the body, and adults who are at risk of GIST coming back after surgical removaL

• GLEEVEC INHIBITS THE ACTIVITY OF THE Kit RECEPTOR TYROSINE KINASE THAT IS MUTATED AND CONSTITUTIVELY ACTIVE IN GISTS
• DRAMATIC RESPONSE TO TREATMENT AFTER AS LITTLE AS 1 MONTH POSSIBLE
• RESISTANCE TO THE DRUG DEVELOPS IN MOST PATIENTS AFTER 2 YEARS (OFTEN AFTER 9 MONTHS), EACH OF THE NEWLY DEVELOPING TUMOURS WILL HAVE A NOVEL SECONDARY POINT MUTATION IN THE Kit GENE

Question 14

BACKUP INHIBITORS OF BCR-ABL FOR PATIENTS WITH GLEEVEC-RESISTANT TUMOURS?

Answer 14

• A DRUG CALLED AMN107
• 20 TIMES MORE POTENT THAN GLEEVEC AGAINST UNMUTATED BCR-ABL
• GLEEVEC RESISTANT BCR-ABL PROTEINS SHOW MORE SENSITIVITY TO INHIBITION BY AMN107
• BUT RESISTANCE CAN DEVELOP TO THIS AS WELL

Question 15

COMPARE THE 1ST, 2ND AND 3RD GENERATION EGFR INHIBITORS

Answer 15

1ST GEN:

• ANILINOQUINAZOLINE CORE BACKBONE STRUCTURE
• BIND REVERSIBLY IN COMPETITION WITH ATP

2ND GEN:

• QUINAZOLINE CORE STRUCTURE
• CONTAIN A COVALENT WARHEAD THAT ENABLES IRREVERSIBLE BINDING, INCREASING POTENCY BUT ALSO TOXICITY

3RD GEN:
- OVERCOME THE ACQUIRED RESISTANCE MUTATION (EGFR-T790M) WITH A COVALENT WARHEAD AND A STRUCTURALLY DISTINCT PYRIMIDINE CORE BACKBONE WHICH BINDS SELECTIVELY

Question 16

EXAMPLES OF HOW RESISTANCE IS DEVELOPED FOR SMALL MOLECULE INHIBITORS?

Answer 16

• MUTATIONS IN THE DRUG TARGET (IMPACTS DRUG BINDING)
• BYPASS SIGNALLING (MAINTAINS ONCOGENIC SIGNALLING DESPITE THE DRUG)
• MUTATIONS IN DOWNSTREAM EFFECTORS (ONCOGENE REARRANGEMENT & ALTERATIONS IN GENE REGULATING CELL CYCLE)

Question 17

BCL2 PATHWAY AND CANCER?

Answer 17

BCL PATHWAY –> ‘HUB OF CELL DEATH’

BCL2 family of proteins is the hallmark of apoptosis regulation. In the last decade, new members of BCL2 gene family were discovered and cloned and were found to be differentially expressed in many types of cancer. BCL2 protein family, through its role in regulation of apoptotic pathways, is possibly related to cancer pathophysiology and resistance to conventional chemotherapy.

BCL2 (and its antiapoptotic orthologues) seems to inhibit apoptosis by the preservation of mitochondrial membrane integrity as its hydrophobic carboxyl-terminal domain is linked to the outer membrane.

Question 18

WHAT IS USED IN CANCER TO TARGETED THE DISREGULATED BCL2 PATHWAY?

Answer 18

BH3 MIMETICS

Question 19

BH3 MIMETICS?

Answer 19

The mitochondrial pathway of apoptosis is regulated by more than a dozen proteins of the BCL-2 family, which is divided into three groups: the pro-apoptotic multi-domain, the anti-apoptotic multi-domain, and the BH3-only pro-apoptotic proteins. Their interactions at the mitochondrial outer membrane ultimately decide if the pore-forming multi-domain pro-apoptotic proteins BAX or BAK will undergo a conformational change, oligomerize, and form pores in the outer mitochondrial membrane (which leads to cell death). . Anti-apoptotic proteins possess a hydrophobic groove that binds the hydrophobic face of the amphipathic, alpha-helical BH3 domain that is present in every BCL-2 family protein.

BH3 mimetics are a class of compounds that compete for this hydrophobic groove to antagonize the function of anti-apoptotic proteins. BH3 mimetics have entered the clinic and even gained regulatory approval for use in cancer.

• predominantly used for lymphoma and leukemia, but also being increasingly used in context of solid tumours
• resistance possible

Question 20

PARP PATHAY AND CNACER

Answer 20

PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer

INHIBITING PARP1 IN BRCA DEFICIENT CELLS RESULTS IN CELL DEATH - SYNTHETIC LETHALITY:

IN NORMAL CELLS: BOTH BASE-EXCISION REPAIR AND HOMOLOGOUS RECOMBINATION ARE AVAILABLE FOR THE REPIR OF DAMAGED DNA

IN CELLS THAT HAVE LOST EITHER BRCA1 OR BRCA2 (E.G. CANCER CELLS WITH BRCA MUTATION): HOMOLOGOUS RECOMBINATION IS NON FUNCTIONAL, BUT BASE EXCISION REPAIR AND OTHER DNA-REPAIR PROCESSES CAN COMPENSATE FOR THAT

IN CELLS THAT HAVE LOST BASE-EXCISION REPAIR BECAUSE OF PARP1 INHIBITION BUT RETAIN AT LEAST ONE FUNCTIONING COPY OF BRCA1 AND BRCA2 GENE, HOMOLOGOUS RECOMBINATION IS INTACT AND CAN COMPENSATE/REPAIR DNA DAMAGE

IN THE CANCER CELLS WEHRE BRCA1 OR BRCA2 FUNCITION IS ABSENT AND WHEN PARP1 IS INHIBITED: CANCER CELLS CANNOT USE HOMOLOGOUS RECOMBINATION OR BASE-EXCISION REPAIR, RESULTING IN CELL DEATH!!!!!

Question 21

The genetic interaction between PARP and BRCA can be described as

Answer 21

SYNTHETIC LETHAL

Question 22

WHAT IS ‘BRCAness’ IN SPORADIC TUMOURS?

Answer 22

• DNA REPAIR PROCESSES ARE DISRUPTED BY NUMEROUS MECHANISMS IN SPORADIC TUMOURS
• SOME SPORADIC TUMOURS SHARE TRAITS WITH THOSE OCCURING IN BRCA1 OR BRCA2 MUTATION CARRIERS (E.G. SHOW SOME RESPONSE TO TREATMENT WITH PARP INHIBITORS)
• Tumours that share molecular features of BRCA-mutant tumours — that is, those with ‘BRCAness’ — may also respond to similar therapeutic approaches. –> CAN HELP SELECT AND PERSONALISE THERAPY BASED ON INDIVIDUAL’S TUMOUR’S PROFILE, MAKE PREDICTIOMNS AND PROGNOSIS

Question 23

DESCRIBE THE FUTURE DIRECTIONS FOR SMALL MMOLECULE TARGETED INHIBITORS

Answer 23

• PERFORM CLINICAL TRIAL BASED ON ctDNA-BASED PRECISION MEDICINE IN MRD (MRD, MINIMAL RESIDUAL DISEASE refers to cancer cells remaining after treatment that can’t be detected by those same scans or tests) AND ADVANCED SETTINGS (Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that is not associated with cells)
• APPLY NOVEL NEXT-GENERATION STRATEGIES, SUCH AS ALLOSTERIC INHIBITION ( a form of noncompetitive inhibition) AND MUTANT-SPECIFIC INHIBITION
• TACKLE DIFFICULT-TO-DRUG KINASES, AND OTHER TARGETS, SUCH AS METABOLISM AND IMMUNO-ONCOLOGY
• TRANSLATE KNOWLEDGE FROM MORE PREDICTIVE NON-CLINICAL MODELS AND FROM REAL-WORLD EVIDENCE

Question 24

CANCER THERAPY IN EVOLUTION?

Answer 24

MOVING FROM EMIPIRICISM TO DESIGN, MORE TAILORED/TARGETED APPROACHES

Question 25

DEVELOPMENT OF VARIOUS KINASE INHIBITORS AS TARGETED APPROACHES TO TREAT CANCER HAS BEEN OCCURING OVER THE LAST:

Answer 25

20 YEARS