HSC Exam Practice

Sample response. Targeted therapy is treatment designed to act on a specific molecular target — typically a disease-causing protein, mutant enzyme, or oncogene product — that is distinct to the disease. For example, vemurafenib (a BRAF inhibitor) specifically inhibits the mutant BRAF V600E kinase found in approximately 50% of melanomas, blocking the constitutive proliferation signal it generates and preferentially killing cancer cells carrying that mutation. Cytotoxic chemotherapy, by contrast, kills all rapidly dividing cells by damaging DNA or disrupting mitosis — it does not discriminate between cancer cells and normal healthy dividing cells (such as bone marrow, hair follicles, and gut epithelium), producing significant off-target side effects including hair loss, immunosuppression, and nausea.

Marking notes. 1 mark — defines targeted therapy as acting on a specific molecular target (accept: specific protein, mutant kinase, receptor, or oncogene product); 1 mark — names a correct targeted therapy example with its specific target (e.g. vemurafenib / BRAF V600E; pembrolizumab / PD-1; CFTR modulators / CFTR protein; imatinib / BCR-ABL); 1 mark — correctly identifies that cytotoxic chemotherapy kills all rapidly dividing cells non-specifically and states a consequence of this non-selectivity (side effects or lack of specificity). Merely stating "targeted = specific, chemo = non-specific" without mechanism earns 1 mark maximum.

Sample response. Statins (e.g. atorvastatin, rosuvastatin) inhibit HMG-CoA reductase — the rate-limiting enzyme in the hepatic cholesterol synthesis (mevalonate) pathway. Blocking this enzyme reduces the liver's production of cholesterol. In response to reduced intracellular cholesterol, hepatocytes upregulate the expression of LDL receptors on their surface. More LDL receptors capture and internalise more LDL particles from the bloodstream, reducing blood LDL concentration. A lower blood LDL means less LDL is available to infiltrate arterial walls, oxidise, and accumulate in macrophages to form foam cells — the core process of atherosclerotic plaque formation. Statins therefore slow the rate of new plaque formation without reversing existing plaques.

Marking notes. 1 mark — correctly names HMG-CoA reductase as the enzyme inhibited; 1 mark — explains reduced hepatic cholesterol synthesis leads to liver upregulating LDL receptors; 1 mark — explains LDL receptor upregulation leads to more LDL being cleared from blood (reduced blood LDL); 1 mark — connects lower blood LDL to slower atherosclerotic plaque formation (less substrate for plaque). Accepting equivalent terminology (e.g. "mevalonate pathway enzyme"). Deduct if student states statins "dissolve" existing plaques — this is incorrect.

Sample response. The PD-1/PD-L1 pathway is a normal immune regulatory mechanism: PD-1 (Programmed Death protein 1) is expressed on cytotoxic T cells. When PD-L1, expressed on healthy tissue cells or activated immune cells, binds PD-1, it delivers an inhibitory signal that suppresses T cell activity — preventing excessive autoimmune tissue damage. Cancer cells exploit this mechanism by upregulating PD-L1 on their surface, binding PD-1 on cytotoxic T cells approaching the tumour, and switching those T cells off — rendering the cancer cells invisible to immune destruction. Pembrolizumab is a monoclonal antibody that binds the PD-1 receptor on T cells, physically blocking the PD-L1/PD-1 interaction. With PD-1 blocked, cancer cells can no longer switch off T cells; the T cells remain cytotoxically active and can now recognise and kill cancer cells, restoring immune-mediated tumour destruction.

Marking notes. 1 mark — correctly describes the normal function of PD-1/PD-L1 (PD-1 on T cells; PD-L1 on cells; inhibitory signal suppresses T cell activity to prevent autoimmunity); 1 mark — explains how cancer cells exploit this (upregulate PD-L1 to switch off cytotoxic T cells / evade immune surveillance); 1 mark — explains pembrolizumab's mechanism (antibody binds PD-1 on T cells, blocks the PD-L1/PD-1 interaction); 1 mark — explains the outcome (T cells remain active, can recognise and kill cancer cells — immune-mediated tumour destruction restored). Must not conflate pembrolizumab with chemotherapy or describe it as "boosting immunity generally."

Sample response. Symptomatic treatment relieves the symptoms of a disease without addressing its underlying cause — for example, insulin injections in Type 1 diabetes replace the missing insulin signal and control blood glucose, but do not restore beta cells or eliminate the autoimmune process destroying them. Curative treatment eliminates the underlying cause of disease — for example, surgical removal of a localised tumour (where complete excision cures the cancer), or CRISPR gene correction of a mutation at its source (theoretical cure for CF or sickle cell disease, as with Casgevy).

Marking notes. 1 mark — correctly defines symptomatic treatment (relieves symptoms, does not address root cause) with a named example; 1 mark — correctly defines curative treatment (eliminates or corrects the underlying cause) with a named example. Accept any valid lesson-sourced example for each category. Analgesics for cancer pain / palliative care counts as symptomatic. Note: CFTR modulators are mechanism-level, not fully curative — do not accept Trikafta as a curative example without qualification that the gene mutation persists.

Sample response. In Type 2 diabetes, pancreatic beta cells are not destroyed — they are functionally exhausted by years of overwork against a background of insulin resistance. The primary driver of that insulin resistance is excess visceral adipose tissue, which secretes pro-inflammatory adipokines (e.g. TNF-α, IL-6) that impair insulin receptor signalling in liver, muscle, and fat. Significant weight loss reduces visceral fat → adipokine signalling normalises → insulin receptor sensitivity is restored → beta cell function can partially recover. Because the beta cells are still present (only functionally impaired), glucose homeostasis can be restored without medication — remission. In Type 1 diabetes, beta cells have been destroyed by autoimmune attack. No amount of weight loss can restore insulin production because the insulin-producing cells no longer exist. The root cause (autoimmune destruction) cannot be reversed by lifestyle modification, so remission via weight loss is not possible in T1D.

Marking notes. 1 mark — correctly identifies that T2D beta cells are functionally exhausted but not destroyed, and that T1D beta cells are destroyed by autoimmune attack; 1 mark — explains the mechanism by which weight loss restores T2D remission (visceral fat reduction → adipokine normalisation → insulin sensitivity restored → beta cell function recovers); 1 mark — explicitly states why this cannot work for T1D (beta cells no longer present / destroyed — weight loss cannot restore something that has been destroyed). Must contrast both diseases explicitly for full marks.

Sample response. (1) CAR-T cell therapy (e.g. tisagenlecleucel) — targets B-cell acute lymphoblastic leukaemia (B-ALL) and other blood cancers. Mechanism: a patient's own T cells are extracted and genetically engineered to express a Chimeric Antigen Receptor (CAR) targeting CD19 on cancer cell surfaces. The modified cells are expanded in culture and reinfused — they seek out and kill cancer cells expressing CD19, producing durable complete remission in some patients. (2) Antisense oligonucleotides (ASOs, e.g. tominersen) — target Huntington's disease. Mechanism: short synthetic DNA/RNA strands bind complementary mutant HTT mRNA produced from the expanded CAG repeat and trigger its degradation via RNase H, reducing the amount of toxic mutant huntingtin protein produced before it can accumulate and aggregate in neurons.

Marking notes. 2 marks per therapy (1 for naming disease, 1 for correct mechanism). Accept any two from the lesson: CAR-T (any blood cancer, CD19 or other tumour antigen target); ASOs (Huntington's disease, HTT mRNA degradation); CRISPR gene editing (sickle cell / CF / cancer — Casgevy, correct DNA mutation); GLP-1 agonists (semaglutide — T2D / obesity — GLP-1 mimicry, insulin secretion + appetite suppression + weight loss). For GLP-1 agonists: accept as emerging if student notes their novel application for obesity/remission beyond standard T2D management. Require both the disease name AND a mechanism for each mark.

Sample response (a) — sweat chloride (3 marks). The Trikafta group showed a large mean decrease in sweat chloride of 41.8 mmol/L compared to virtually no change in the placebo group (−0.5 mmol/L), a difference of 41.3 mmol/L. Sweat chloride concentration is the gold-standard biomarker for CFTR function — in CF, defective CFTR means Cl− is not reabsorbed from sweat ducts, so sweat chloride is high (>60 mmol/L diagnostic threshold). The large decrease in the Trikafta group directly demonstrates that Trikafta is restoring CFTR function at the molecular level in epithelial cells — correctors are helping more F508del CFTR protein reach the membrane and potentiators are keeping the channel open, allowing Cl− to be transported normally.

Marking notes (a). 1 mark — describes the pattern (Trikafta = large decrease ~41.8 mmol/L; placebo = negligible change ~−0.5 mmol/L; quotes the 41.3 mmol/L difference); 1 mark — explains sweat chloride as a biomarker for CFTR function (high sweat Cl− = defective CFTR; decrease = restored CFTR function); 1 mark — connects the sweat chloride result to the molecular mechanism of Trikafta (correctors + potentiator restoring CFTR function at the epithelial cell membrane level).

Sample response (b) — effectiveness evaluation (3 marks). The data demonstrate strong effectiveness across both molecular/physiological and quality-of-life domains. At the physiological level: lung function improved by a mean of 13.8 percentage points (ppFEV1) in the Trikafta group versus a slight decline of 0.4 pp in placebo — a clinically significant 14.2 pp difference. For a disease measured by annual declines of 1–2 pp, this represents reversal of multiple years' worth of deterioration. Pulmonary exacerbation rate fell 62% (from 0.98 to 0.37 per patient-year), substantially reducing hospitalisations and antibiotic courses. At the quality-of-life level: 73.5% of Trikafta patients reported improved respiratory symptoms versus 41.2% on placebo — a 32.3 pp difference. Taken together, Trikafta is highly effective at improving the key drivers of CF morbidity and patient experience. However, the trial period was only 24 weeks — the long-term durability of these effects, and whether lung function improvement is maintained over years, requires longer follow-up data.

Marking notes (b). 1 mark — references at least two rows of data with specific figures (e.g. ppFEV1 +14.2 pp difference AND exacerbation rate −62%); 1 mark — distinguishes between physiological outcome measures (ppFEV1, exacerbation rate, sweat chloride) and quality-of-life outcome (CFQ-R score) in the evaluation; 1 mark — makes an evaluative statement about effectiveness that goes beyond description (e.g. notes the clinical significance of the ppFEV1 change, notes a limitation such as trial duration, or concludes that Trikafta is clearly effective based on the totality of data).

Sample response (c) — not a cure (2 marks). Trikafta is not a cure for CF because it does not correct the underlying F508del gene mutation. Every cell in the patient's body still carries the same mutant CFTR gene — Trikafta improves the function of the dysfunctional CFTR protein it encodes, but if treatment is stopped, the protein reverts to being misfolded and the disease returns. A cure would require either permanently correcting the mutation in the patient's genome (e.g. via CRISPR gene editing in lung stem cells) or replacing all affected tissue. Trikafta is a mechanism-level treatment — transformative in its clinical effects but requiring lifelong daily administration.

Marking notes (c). 1 mark — correctly states that Trikafta does not correct the F508del gene mutation (mutation persists in every cell); 1 mark — correctly explains the consequence: disease returns without ongoing treatment / protein function only restored while drug is present (so it is treatment, not cure). Do not award if student conflates gene-level and protein-level correction.

Sample response. The claim conflates molecular specificity with overall effectiveness — these are related but not synonymous. It is correct that pharmacological treatments act on specific molecular targets, and this specificity can produce precise, powerful effects: statins inhibit HMG-CoA reductase to lower blood LDL and slow atherosclerosis; BRAF inhibitors target the BRAF V600E kinase in melanoma; CFTR modulators restore CFTR protein function in cystic fibrosis. These drugs act at the molecular level, with clear mechanistic rationale. However, acting on a specific molecular target does not automatically make a treatment more effective than lifestyle modification. The DiRECT trial demonstrated that structured dietary weight management produced Type 2 diabetes remission in 46% of patients at 12 months — compared to 4% in the standard care (largely pharmacological) group. This is not because lifestyle modification lacks molecular specificity: weight loss reduces visceral adipose tissue → pro-inflammatory adipokine secretion falls → insulin receptor signalling is restored → beta cells recover. Lifestyle modification acts through understood biological mechanisms at multiple molecular levels simultaneously — it is arguably more mechanistically comprehensive than any single drug. The distinction is that lifestyle modification addresses the root metabolic cause of T2D, while most T2D pharmacotherapy (including metformin) acts at the mechanism or progression level, managing glucose without reversing insulin resistance. The claim is therefore incorrect as an absolute statement. Pharmacological treatments that target molecular mechanisms are often highly effective — but effectiveness depends on the match between the treatment's level of intervention and the disease's primary driver. For T2D (a nutritional/metabolic disease), lifestyle modification that removes the nutritional excess driving disease is more effective per se at achieving remission than any single approved drug. The claim would be more defensible for diseases where lifestyle modification has limited reach — such as CF (mutation in every cell) or BRAF V600E melanoma (requires pharmacological kinase inhibition). Effectiveness is disease- and context-dependent, not a function of molecular target specificity alone.

Marking notes. 1 mark — acknowledges the correct element of the claim: pharmacological treatments can act with high molecular specificity (names a correct example with mechanism). 1 mark — uses the DiRECT trial data (quotes the 46% vs 4% remission figures) to challenge the claim that pharmacological = more effective. 1 mark — explains that lifestyle modification also acts through understood molecular mechanisms (visceral fat reduction → adipokine normalisation → insulin resistance reversal) — it is not "non-scientific" or non-specific. 1 mark — reaches an explicit evaluative judgement that the claim is incorrect as an absolute statement and that effectiveness is disease- and context-dependent. A response that argues "both have roles" without the DiRECT data and without challenging the molecular-specificity premise earns a maximum of 2 marks.